Imidazopyridazine derivative having kinase inhibitory activity and pharmaceutical agent thereof

ABSTRACT

The present invention provides an imidazopyridazine derivative compound having a potent kinase inhibitory activity and a pharmaceutical agent thereof useful for treatment or prevention of cancer and the like. One such compound is represented by the formula: 
                         
or a salt thereof or a prodrug thereof. The pharmaceutical agent contains the imidazopyridazine derivative compound or a prodrug thereof, which is a kinase (VEGFR, VEGFR2, PDGFR, Raf) inhibitor, an angiogenesis inhibitor, an agent for the prophylaxis or treatment of cancer, a cancer growth inhibitor, or a cancer metastasis suppressor.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of application Ser. No. 12/064,903,filed Feb. 26, 2008, which is a U.S. National Stage of PCT/JP2007/065681filed Aug. 3, 2007, which applications are incorporated herein byreference.

TECHNICAL FIELD

The present invention relates to fused heterocyclic derivatives and usethereof. More particularly, the present invention relates toimidazopyridazine derivatives having potent kinase inhibitory activityand useful for the prophylaxis or treatment of cancer and the like.

BACKGROUND OF THE INVENTION

For a solid tumor to grow to a certain size or above, angiogenesis isessential for ensuring sufficient supply of nutrition and oxygen tocancer cell (see, for example, New England Journal of Medicine, 1971,vol. 285, No. 21, pp. 1182-1186). One of the important factors causingangiogenesis toward tumor, a vascular endothelial growth factor (VEGF)is known. VEGF is bound to a vascular endothelial growth factor receptor(VEGFR) expressed on vascular endothelial cells and transmits signal forcell growth (see, for example, Endocrine Reviews, 1997, vol. 18, No. 1,pp. 4-25). Accordingly, inhibition of the VEGF-VEGFR signal transductionsystem is considered to enable suppression of angiogenesis and tumorgrowth (see, for example, Drug Discovery Today, 2001, vol. 6, No. 19,pp. 1005-1024). Moreover, since tumor blood vessels are involved incancer hematogenous metastasis, inhibition of angiogenesis is consideredto be effective for suppression of cancer metastasis.

As compounds inhibiting receptor-type tyrosine kinase including VEGFR,phthalazine derivatives (see, for example, WO 98/35958),pyrrole-substituted 2-indolinone derivatives see, for example, WO01/60814), quinazoline derivatives (see, for example, WO 01/32651),ω-carboxyaryl-substituted diphenylurea derivatives (see, for example, WO00/42012), quinoline derivatives and quinazoline derivatives (see, forexample, WO 00/43366), nitrogen-containing aromatic ring derivatives(see, for example, WO 02/32872) and the like are known.

DISCLOSURE OF THE INVENTION

A kinase inhibitor superior in the affinity for kinase, efficacyexpression, pharmacokinetics, solubility, interaction with otherpharmaceutical products, safety and stability is expected to show atherapeutically superior effect. At present, however, such inhibitorsuperior in the affinity for kinase, and sufficiently satisfactory inthe efficacy expression, pharmacokinetics, solubility, interaction withother pharmaceutical products, safety and stability has not been found.Thus, there is a demand for the development of a compound having asuperior kinase inhibitory activity, and sufficiently satisfactory as apharmaceutical product. Accordingly, an object of the present inventionis to provide a compound having a superior kinase inhibitory activity,low toxic and sufficiently satisfactory as a pharmaceutical product.

The present inventors have conducted intensive studies in an attempt tosolve the above-mentioned problems and found that a compound representedby the following formula or a salt thereof has a superior kinaseinhibitory activity, which resulted in the completion of the presentinvention.

Accordingly, the present invention provides the following.

[1] A compound represented by the formula (I):

whereinring Y is an optionally substituted cyclic group;X is —O—, —S—, —S(O)—, —S(O)₂— or —NR— (wherein R is a hydrogen atom ora substituent);R¹ is a hydrogen atom or a substituent;R² is a hydrogen atom or a substituent;R³ is a hydrogen atom or a substituent;R⁴ is a hydrogen atom or a substituent;provided thatwhen R¹ is other than an optionally substituted amino, ring Y is acyclic group substituted by an optionally substituted amino, wherein thecyclic group is optionally further substituted, and that

-   methyl [6-(phenylthio)imidazo[1,2-b]pyridazin-2-yl]carbamate,-   methyl [6-(phenylsulfinyl)imidazo[1,2-b]pyridazin-2-yl]carbamate,-   ethyl 6-(4-acetamidophenoxy)imidazo[1,2-b]pyridazine-2-carboxylate,-   ethyl    6-[4-(4-acetylpiperazin-1-yl)phenoxy]imidazo[1,2-b]pyridazine-2-carboxylate,-   N-[1-(imidazo[1,2-b]pyridazin-6-ylamino)-2,5-dioxo-1,2,5,6,7,8-hexahydroquinolin-3-yl]benzamide,-   N-[1-(imidazo[1,2-b]pyridazin-6-ylamino)-7,7-dimethyl-2,5-dioxo-1,2,5,6,7,8-hexahydroquinolin-3-yl]benzamide,-   N-[1-(imidazo[1,2-b]pyridazin-6-ylamino)-2,5-dioxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl]benzamide,-   N-[1-(imidazo[1,2-b]pyridazin-6-ylamino)-7-methyl-2,5-dioxo-1,2,5,6,7,8-hexahydroquinolin-3-yl]benzamide,-   N-[(5E)-5-(imidazo[1,2-b]pyridazin-6-ylhydrazono)-7-methyl-2-oxo-4a,5,6,7,8,8a-hexahydro-2H-chromen-3-yl]benzamide,-   4-methoxybenzyl    (6R,7R)-3-(imidazo[1,2-b]pyridazin-6-ylthio)-8-oxo-7-[(phenylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate,-   4-[(3-methoxy-2-phenylimidazo[1,2-b]pyridazin-6-yl)thio]-N,N-dimethylaniline,-   3-methoxy-6-(3-nitrophenoxy)-2-phenylimidazo[1,2-b]pyridazine,-   3-[(3-methoxy-2-phenylimidazo[1,2-b]pyridazin-6-yl)oxy]aniline, and-   3-[(3-methoxy-2-phenylimidazo[1,2-b]pyridazin-6-yl)oxy]-N,N-dimethylaniline    are excluded,    or a salt thereof.    [2] The compound of the above-mentioned [1], wherein a compound    represented by the formula (II):

whereinring Ya is an optionally substituted cyclic group;Xa is —O—, —S—, —S(O)—, —S(O)₂— or —NR^(a)— (wherein R^(a) is a hydrogenatom or a substituent);R^(1a) is an optionally substituted amino;R^(2a) is a hydrogen atom or a substituent;R^(3a) is a hydrogen atom or a substituent;R^(4a) is a hydrogen atom or a substituent;provided that

-   methyl [6-(phenylthio)imidazo[1,2-b]pyridazin-2-yl]carbamate and-   methyl [6-(phenylsulfinyl)imidazo[1,2-b]pyridazin-2-yl]carbamate are    excluded,    or a salt thereof.    [3] The compound of the above-mentioned [2], wherein R^(1a) is    (1) amino,    (2) optionally substituted alkylcarbonylamino,    (3) optionally substituted alkenylcarbonylamino,    (4) optionally substituted alkynylcarbonylamino,    (5) optionally substituted cycloalkylcarbonylamino,    (6) optionally substituted cycloalkyl-alkylcarbonylamino,    (7) optionally substituted 6-membered heterocyclyl-carbonylamino,    (8) optionally substituted aminocarbonylamino,    (9) optionally substituted alkoxycarbonylamino,    (10) optionally substituted alkylsulfonylamino,    (11) optionally substituted cycloalkylsulfonylamino,    (12) optionally substituted arylamino, or    (13) optionally substituted heterocyclylamino.    [4] The compound of the above-mentioned [2], wherein R^(1a) is    (1) amino,    (2) C₁₋₄ alkyl-carbonylamino optionally substituted by 1 to 3    substituents selected from    -   (a) a halogen atom,    -   (b) hydroxy,    -   (c) C₁₋₄ alkoxy,    -   (d) C₁₋₄ alkyl-carbonyloxy,    -   (e) C₁₋₄ alkylamino,    -   (f) di-C₁₋₄ alkylamino,    -   (g) C₁₋₄ alkylsulfonyl, and    -   (h) a 6-membered heterocyclic group optionally having 1 to 3        C₁₋₄ alkyl,        (3) C₂₋₄ alkenyl-carbonylamino optionally having C₁₋₄ alkoxy,        (4) C₂₋₄ alkynyl-carbonylamino,        (5) C₃₋₆ cycloalkyl-carbonylamino optionally substituted by 1 to        4 substituents selected from    -   (a) a halogen atom,    -   (b) hydroxy,    -   (c) C₁₋₄ alkyl optionally having hydroxy,    -   (d) C₁₋₄ alkoxy,    -   (e) C₁₋₄ alkoxy-carbonyl, and    -   (f) C₁₋₄ alkyl-carbonyloxy,        (6) C₃₋₆ cycloalkyl-C₁₋₄ alkyl-carbonylamino,        (7) 6-membered heterocyclyl-carbonylamino optionally substituted        by 1 to 3 substituents selected from    -   (a) a halogen atom,    -   (b) cyano, and    -   (c) C₁₋₄ alkyl optionally having 1 to 3 halogen atoms,        (8) aminocarbonylamino optionally substituted by 1 or 2        substituents selected from    -   (a) C₁₋₄ alkyl optionally having 1 to 3 C₁₋₄ alkoxy optionally        having 1 to 3 hydroxy, and    -   (b) C₁₋₄ alkoxy,        (9) C₁₋₄ alkoxy-carbonylamino optionally substituted by 1 to 3        halogen atoms,        (10) C₁₋₄ alkylsulfonylamino,        (11) C₃₋₆ cycloalkylsulfonylamino,        (12) C₆₋₁₀ arylamino, or        (13) heterocyclylamino optionally substituted by 1 to 3        substituents selected from    -   (a) a halogen atom, and    -   (b) C₁₋₄ alkylamino.        [5] The compound of the above-mentioned [2], wherein R^(2a) is a        hydrogen atom.        [6] The compound of the above-mentioned [2], wherein R^(3a) is a        hydrogen atom.        [7] The compound of the above-mentioned [2], wherein R^(4a) is a        hydrogen atom.        [8] The compound of the above-mentioned [2], wherein Xa is —O—,        —S— or —NH—.        [9] The compound of the above-mentioned [2], wherein ring Ya is        an optionally substituted aromatic hydrocarbon group or an        optionally substituted aromatic heterocyclic group.        [10] The compound of the above-mentioned [2], wherein ring Ya is        (1) C₆₋₁₀ aryl optionally substituted by 1 to 3 substituents        selected from    -   (a) a halogen atom,    -   (b) C₁₋₄ alkyl,    -   (c) C₁₋₄ alkoxy,    -   (d) amino optionally substituted by the substituents selected        from        -   (i) C₁₋₄ alkyl optionally substituted by a 5-membered            aromatic heterocyclic group optionally substituted by 1 to 3            C₁₋₄ alkyl,        -   (ii) C₁₋₄ alkyl-carbonyl optionally substituted by 1 to 3            substituents selected from            -   (i′) hydroxy,            -   (ii′) C₁₋₄ alkylsulfonyl, and            -   (iii′) a 6-membered aromatic heterocyclic group,        -   (iii) C₂₋₄ alkenyl-carbonyl optionally substituted by C₆₋₁₀            aryl,        -   (iv) C₂₋₄ alkynyl-carbonyl optionally substituted by C₆₋₁₀            aryl,        -   (v) C₃₋₆ cycloalkyl-carbonyl,        -   (vi) C₃₋₆ cycloalkenyl-carbonyl,        -   (vii) C₆₋₁₀ aryl-carbonyl optionally substituted by 1 to 3            substituents selected from            -   (i′) a halogen atom,            -   (ii′) C₁₋₄ alkyl optionally substituted by 1 to 3                substituents selected from a halogen atom, cyano,                hydroxy and C₃₋₆ cycloalkyl,            -   (iii′) C₃₋₆ cycloalkyl optionally substituted by cyano,            -   (iv′) C₁₋₄ alkoxy optionally substituted by 1 to 5                halogen atoms,            -   (v′) C₁₋₄ alkoxy-carbonyl, and            -   (vi′) a 5- or 6-membered heterocyclic group optionally                substituted by cyano or oxo,        -   (viii) 5- or 6-membered heterocyclyl-carbonyl containing, as            ring-constituting atom, 1 to 3 heteroatoms selected from            oxygen atom, sulfur atom and nitrogen atom besides carbon            atoms, which is optionally substituted by 1 to 3            substituents selected from            -   (i′) a halogen atom,            -   (ii′) C₁₋₄ alkyl optionally substituted by 1 to 3                substituents selected from a halogen atom, cyano,                hydroxy and C₁₋₄ alkoxy,            -   (iii′) C₆₋₁₀ aryl,            -   (iv′) C₆₋₁₀ aryl-C₁₋₄ alkyl,            -   (v′) C₁₋₄ alkoxy optionally substituted by C₁₋₄ alkoxy,            -   (vi′) C₁₋₄ alkylsulfonyl,            -   (vii′) C₁₋₄ alkyl-carbonyl, and            -   (viii′) oxo,        -   (ix) aromatic fused heterocyclyl-carbonyl,        -   (x) C₁₋₄ alkyl-aminocarbonyl,        -   (xi) C₆₋₁₀ aryl-aminocarbonyl optionally substituted by C₁₋₄            alkyl optionally substituted by 1 to 3 halogen atoms,        -   (xii) C₁₋₄ alkoxy-aminocarbonyl,        -   (xiii) 5-membered heterocyclyl-aminocarbonyl optionally            substituted by 1 to 3 substituents selected from C₁₋₄ alkyl            and C₆₋₁₀ aryl,        -   (xiv) aminothiocarbonyl optionally substituted by C₆₋₁₀            aryl-C₁₋₄ alkyl-carbonyl, and        -   (xv) 5-membered aromatic heterocyclyl-sulfonyl optionally            substituted by 1 to 3 C₁₋₄ alkyl,    -   (e) C₁₋₄ alkyl-aminocarbonyl optionally having C₆₋₁₀ aryl,    -   (f) 5-membered heterocyclyl-aminocarbonyl optionally substituted        by 1 to 3 substituents selected from C₁₋₄ alkyl and C₆₋₁₀ aryl,    -   (g) C₆₋₁₀ aryl-aminocarbonyl optionally substituted by C₁₋₄        alkyl optionally substituted by 1 to 3 substituents selected        from a halogen atom and cyano,    -   (h) carboxy, and    -   (i) nitro,        (2) monocyclic aromatic heterocycle optionally substituted by 1        to 3 substituents selected from    -   (a) a halogen atom, and    -   (b) C₆₋₁₀ aryl-carbonylamino optionally substituted by C₁₋₄        alkyl optionally substituted by 1 to 3 halogen atoms, or        (3) fused aromatic heterocycle optionally substituted by 1 to 3        substituents selected from    -   (a) C₁₋₄ alkyl, and    -   (b) C₆₋₁₀ arylamino optionally substituted by C₁₋₄ alkyl        optionally substituted by 1 to 3 halogen atoms.        [11] A compound selected from the group consisting of:-   N-{3-[(2-{[2-(methylamino)pyrimidin-4-yl]amino}imidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide;-   N-[2-chloro-5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide;-   N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide;-   N-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-2,4-dimethyl-1,3-thiazole-5-carboxamide;-   N-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-2,5-dimethyl-1,3-oxazole-4-carboxamide;-   N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide;-   N-[3-({2-[(N,N-dimethylglycyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide;-   N-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}sulfanyl)phenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide;-   N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-1-ethyl-3-methyl-1H-pyrazole-4-carboxamide;-   N-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]benzamide;-   N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-1,3-dimethyl-1H-pyrazole-4-carboxamide;-   N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-1-ethyl-1H-pyrazole-5-carboxamide;-   N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-3-methoxy-1-methyl-1H-pyrazole-5-carboxamide;-   N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-3-ethyl-1-methyl-1H-pyrazole-5-carboxamide;-   N-[2-chloro-5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-1-ethyl-3-methyl-1H-pyrazole-4-carboxamide;-   N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-1-methyl-1H-pyrazole-5-carboxamide;-   N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-2,4-dimethyl-1,3-oxazole-5-carboxamide;-   N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-2-ethyl-4-methyl-1,3-oxazole-5-carboxamide;-   N-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-3-(trifluoromethyl)benzamide;-   3-(1-cyano-1-methylethyl)-N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]benzamide;-   N-[3-({2-[(N,N-dimethylglycyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-3-(trifluoromethyl)benzamide;-   N-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}thio)phenyl]-3-(trifluoromethyl)benzamide;    and-   N-{6-[3-({[3-(trifluoromethyl)phenyl]carbamoyl}amino)phenoxy]imidazo[1,2-b]pyridazin-2-yl}cyclopropanecarboxamide,    or a salt thereof.    [12] The compound of the above-mentioned [1], which is a compound of    the formula (III):

whereinring Yb is a cyclic group substituted by an optionally substitutedamino, wherein the cyclic group is optionally further substituted;Xb is —O—, —S—, —S(O)—, —S(O)₂— or —NR^(b)— (wherein R^(b) is a hydrogenatom or a substituent);R^(1b) is a hydrogen atom or a substituent (provided that an optionallysubstituted amino is excluded);R^(2b) is a hydrogen atom or a substituent;R^(3b) is a hydrogen atom or a substituent;R^(4b) is a hydrogen atom or a substituent;provided that

-   ethyl 6-(4-acetamidophenoxy)imidazo[1,2-b]pyridazine-2-carboxylate,-   ethyl    6-[4-(4-acetylpiperazin-1-yl)phenoxy]imidazo[1,2-b]pyridazine-2-carboxylate,-   N-[1-(imidazo[1,2-b]pyridazin-6-ylamino)-2,5-dioxo-1,2,5,6,7,8-hexahydroquinolin-3-yl]benzamide,-   N-[1-(imidazo[1,2-b]pyridazin-6-ylamino)-7,7-dimethyl-2,5-dioxo-1,2,5,6,7,8-hexahydroquinolin-3-yl]benzamide,-   N-[1-(imidazo[1,2-b]pyridazin-6-ylamino)-2,5-dioxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl]benzamide,-   N-[1-(imidazo[1,2-b]pyridazin-6-ylamino)-7-methyl-2,5-dioxo-1,2,5,6,7,8-hexahydroquinolin-3-yl]benzamide,-   N-[(5E)-5-(imidazo[1,2-b]pyridazin-6-ylhydrazono)-7-methyl-2-oxo-4a,5,6,7,8,8a-hexahydro-2H-chromen-3-yl]benzamide,-   4-methoxybenzyl    (6R,7R)-3-(imidazo[1,2-b]pyridazin-6-ylthio)-8-oxo-7-[(phenylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate,-   4-[(3-methoxy-2-phenylimidazo[1,2-b]pyridazin-6-yl)thio]-N,N-dimethylaniline,    3-methoxy-6-(3-nitrophenoxy)-2-phenylimidazo[1,2-b]pyridazine,-   3-[(3-methoxy-2-phenylimidazo[1,2-b]pyridazin-6-yl)oxy]aniline, and-   3-[(3-methoxy-2-phenylimidazo[1,2-b]pyridazin-6-yl)oxy]-N,N-dimethylaniline    are excluded,    or a salt thereof.    [13] A prodrug of the compound of the above-mentioned [1].    [14] A pharmaceutical agent comprising the compound of the    above-mentioned [1] or a prodrug thereof.    [15] The pharmaceutical agent of the above-mentioned [14], which is    a kinase inhibitor.    [16] The pharmaceutical agent of the above-mentioned [14], which is    an inhibitor of vascular endothelial growth factor receptor (VEGFR).    [17] The pharmaceutical agent of the above-mentioned [14], which is    an inhibitor of vascular endothelial growth factor receptor (VEGFR)    2.    [18] The pharmaceutical agent of the above-mentioned [14], which is    an inhibitor of platelet-derived growth factor receptor (PDGFR).    [19] The pharmaceutical agent of the above-mentioned [14], which is    a Raf inhibitor.    [20] The pharmaceutical agent of the above-mentioned [14], which is    an angiogenesis inhibitor.    [21] The pharmaceutical agent of the above-mentioned [14], which is    an agent for the prophylaxis or treatment of cancer.    [22] The pharmaceutical agent of the above-mentioned [14], which is    a cancer growth inhibitor.    [23] The pharmaceutical agent of the above-mentioned [14], which is    a cancer metastasis suppressor.    [24] A method for the prophylaxis or treatment of cancer, which    comprises administering an effective amount of a compound of the    formula (I):

whereinring Y is an optionally substituted cyclic group;X is —O—, —S—, —S(O)—, —S(O)₂— or —NR— (wherein R is a hydrogen atom ora substituent);R¹ is a hydrogen atom or a substituent;R² is a hydrogen atom or a substituent;R³ is a hydrogen atom or a substituent;R⁴ is a hydrogen atom or a substituent;provided thatwhen R¹ is other than an optionally substituted amino, ring Y is acyclic group substituted by an optionally substituted amino, wherein thecyclic group is optionally further substituted, and that

-   methyl [6-(phenylthio)imidazo[1,2-b]pyridazin-2-yl]carbamate,-   methyl [6-(phenylsulfinyl)imidazo[1,2-b]pyridazin-2-yl]carbamate,-   ethyl 6-(4-acetamidophenoxy)imidazo[1,2-b]pyridazine-2-carboxylate,-   ethyl    6-[4-(4-acetylpiperazin-1-yl)phenoxy]imidazo[1,2-b]pyridazine-2-carboxylate,-   N-[1-(imidazo[1,2-b]pyridazin-6-ylamino)-2,5-dioxo-1,2,5,6,7,8-hexahydroquinolin-3-yl]benzamide,-   N-[1-(imidazo[1,2-b]pyridazin-6-ylamino)-7,7-dimethyl-2,5-dioxo-1,2,5,6,7,8-hexahydroquinolin-3-yl]benzamide,-   N-[1-(imidazo[1,2-b]pyridazin-6-ylamino)-2,5-dioxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl]benzamide,-   N-[1-(imidazo[1,2-b]pyridazin-6-ylamino)-7-methyl-2,5-dioxo-1,2,5,6,7,8-hexahydroquinolin-3-yl]benzamide,-   N-[(5E)-5-(imidazo[1,2-b]pyridazin-6-ylhydrazono)-7-methyl-2-oxo-4a,5,6,7,8,8a-hexahydro-2H-chromen-3-yl]benzamide,-   4-methoxybenzyl    (6R,7R)-3-(imidazo[1,2-b]pyridazin-6-ylthio)-8-oxo-7-[(phenylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate,-   4-[(3-methoxy-2-phenylimidazo[1,2-b]pyridazin-6-yl)thio]-N,N-dimethylaniline,    3-methoxy-6-(3-nitrophenoxy)-2-phenylimidazo[1,2-b]pyridazine,-   3-[(3-methoxy-2-phenylimidazo[1,2-b]pyridazin-6-yl)oxy]aniline, and-   3-[(3-methoxy-2-phenylimidazo[1,2-b]pyridazin-6-yl)oxy]-N,N-dimethylaniline    are excluded,    or a salt thereof or a prodrug thereof to the mammal.    [25] Use of a compound of the formula (I) for the production of an    agent for the prophylaxis or treatment of cancer:

whereinring Y is an optionally substituted cyclic group;X is —O—, —S—, —S(O)—, —S(O)₂— or —NR— (wherein R is a hydrogen atom ora substituent);R¹ is a hydrogen atom or a substituent;R² is a hydrogen atom or a substituent;R³ is a hydrogen atom or a substituent;R⁴ is a hydrogen atom or a substituent;provided thatwhen R¹ is other than an optionally substituted amino, ring Y is acyclic group substituted by an optionally substituted amino, wherein thecyclic group is optionally further substituted, and that

-   methyl [6-(phenylthio)imidazo[1,2-b]pyridazin-2-yl]carbamate,-   methyl [6-(phenylsulfinyl)imidazo[1,2-b]pyridazin-2-yl]carbamate,-   ethyl 6-(4-acetamidophenoxy)imidazo[1,2-b]pyridazine-2-carboxylate,-   ethyl    6-[4-(4-acetylpiperazin-1-yl)phenoxy]imidazo[1,2-b]pyridazine-2-carboxylate,-   N-[1-(imidazo[1,2-b]pyridazin-6-ylamino)-2,5-dioxo-1,2,5,6,7,8-hexahydroquinolin-3-yl]benzamide,-   N-[1-(imidazo[1,2-b]pyridazin-6-ylamino)-7,7-dimethyl-2,5-dioxo-1,2,5,6,7,8-hexahydroquinolin-3-yl]benzamide,-   N-[1-(imidazo[1,2-b]pyridazin-6-ylamino)-2,5-dioxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl]benzamide,-   N-[1-(imidazo[1,2-b]pyridazin-6-ylamino)-7-methyl-2,5-dioxo-1,2,5,6,7,8-hexahydroquinolin-3-yl]benzamide,-   N-[(5E)-5-(imidazo[1,2-b]pyridazin-6-ylhydrazono)-7-methyl-2-oxo-4a,5,6,7,8,8a-hexahydro-2H-chromen-3-yl]benzamide,-   4-methoxybenzyl    (6R,7R)-3-(imidazo[1,2-b]pyridazin-6-ylthio)-8-oxo-7-[(phenylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate,-   4-[(3-methoxy-2-phenylimidazo[1,2-b]pyridazin-6-yl)thio]-N,N-dimethylaniline,    3-methoxy-6-(3-nitrophenoxy)-2-phenylimidazo[1,2-b]pyridazine,-   3-[(3-methoxy-2-phenylimidazo[1,2-b]pyridazin-6-yl)oxy]aniline, and-   3-[(3-methoxy-2-phenylimidazo[1,2-b]pyridazin-6-yl)oxy]-N,N-dimethylaniline    are excluded,    or a salt thereof or a prodrug thereof.

The present invention also includes the following.

[26] A compound of the formula (IV):

wherein ring Y is an optionally substituted cyclic group;X is —O—, —S—, —S(O)—, —S(O)₂— or —NR— (wherein R is a hydrogen atom ora substituent);R¹ is a hydrogen atom or a substituent;R² is a hydrogen atom or a substituent;R³ is a hydrogen atom or a substituent;R⁴ is a hydrogen atom or a substituent;provided thatwhere R¹ is other than an optionally substituted amino, ring Y is acyclic group substituted by an optionally substituted amino, wherein thecyclic group is optionally further substituted,or a salt thereof.[27] A kinase inhibitor, which comprises the compound of theabove-mentioned [26] or a prodrug thereof.[28] The kinase inhibitor of the above-mentioned [27], wherein thekinase is a vascular endothelial growth factor receptor (VEGFR).[29] The kinase inhibitor of the above-mentioned [27], wherein thekinase is a vascular endothelial growth factor receptor (VEGFR) 2.[30] The kinase inhibitor of the above-mentioned [27], wherein thekinase is a platelet-derived growth factor receptor (PDGFR).[31] The kinase inhibitor of the above-mentioned [27], wherein thekinase is a Raf.[32] An angiogenesis inhibitor, which comprises the compound of theabove-mentioned [26] or a prodrug thereof.[33] An agent for the prophylaxis or treatment of cancer, whichcomprises the compound of the above-mentioned [26] or a prodrug thereof.[34] A cancer growth inhibitor, which comprises the compound of theabove-mentioned [26] or a prodrug thereof.[35] A cancer metastasis suppressor, which comprises the compound of theabove-mentioned [26] or a prodrug thereof.[36] A method for the prophylaxis or treatment of cancer, whichcomprises administering an effective amount of the compound of theabove-mentioned [26] or a prodrug thereof to the mammal.[37] Use of the compound of the above-mentioned [26] or a prodrugthereof for the production of an agent for the prophylaxis or treatmentof cancer.

EFFECT OF THE INVENTION

The compounds represented by the formulas (I) to (IV) of the presentinvention or salts thereof or prodrugs thereof have strong inhibitoryactivity against kinases such as vascular endothelial growth factorreceptor, platelet-derived growth factor receptor and the like, and havestrong angiogenesis inhibitory activity. Therefore, they can provide aclinically useful agent for the prophylaxis or treatment of cancer, acancer growth inhibitor, or a cancer metastasis suppressor. Furthermore,compounds represented by the formulas (I) to (IV) of the presentinvention or salts thereof or prodrugs thereof can provide clinicallyuseful agents for the prophylaxis or treatment for applications ondiseases other than cancer such as chronic rheumatism, diabeticretinopathy and the like, and have excellent efficacy expression,pharmacokinetics, solubility, interaction with other pharmaceuticalproducts, safety and stability.

Hereinafter the present invention is explained in detail.

A compound represented by the formula (I) (hereinafter to be referred toas compound (I)) and a compound represented by the formula (IV)(hereinafter to be referred to as compound (IV)) of the presentinvention are explained.

In compounds (I) and (IV), examples of the “cyclic group” of the“optionally substituted cyclic group” for ring Y include aromatichydrocarbon group, aromatic heterocyclic group (e.g., monocyclicaromatic heterocyclic group, fused aromatic heterocyclic group),non-aromatic cyclic hydrocarbon group, non-aromatic heterocyclic group,fused ring group thereof and the like.

Examples of the aromatic hydrocarbon group include C₆₋₁₄ aryl and thelike. Specifically, phenyl, 1-naphthyl, 2-naphthyl, biphenylyl, anthryl,phenanthryl, acenaphthylenyl and the like can be mentioned.

Examples of the monocyclic aromatic heterocyclic group include 5- to7-membered monocyclic aromatic heterocyclic group containing, asring-constituting atom, 1 to 4 heteroatoms selected from oxygen atom,sulfur atom and nitrogen atom besides carbon atoms, and the like.

Examples of the monocyclic aromatic heterocyclic group specificallyinclude furyl (e.g., 2-furyl, 3-furyl), thienyl (e.g., 2-thienyl,3-thienyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl(e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl),pyridazinyl (e.g., 3-pyridazinyl, 4-pyridazinyl), pyrazinyl (e.g.,2-pyrazinyl), pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl),imidazolyl (e.g., 1-imidazolyl, 2-imidazolyl, 4-imidazolyl,5-imidazolyl), pyrazolyl (e.g., 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl),thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), isothiazolyl,oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isoxazolyl,oxadiazolyl (e.g., 1,2,4-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl),thiadiazolyl (e.g., 1,3,4-thiadiazol-2-yl), triazolyl (e.g.,1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,3-triazol-1-yl,1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl), tetrazolyl (e.g.,tetrazol-1-yl, tetrazol-5-yl), triazinyl and the like.

Examples of the fused aromatic heterocyclic group include a group formedby fusion of 5- to 7-membered monocyclic aromatic heterocyclic groupcontaining, as ring-constituting atom, 1 to 4 heteroatoms selected fromoxygen atom, sulfur atom and nitrogen atom besides carbon atoms, and thelike, and C₆₋₁₄ aryl and the like; a group formed by fusion of theabove-mentioned 5- to 7-membered monocyclic aromatic heterocyclicgroups, and the like.

Examples of the fused aromatic heterocyclic group specifically includequinolyl (e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl, isoquinolyl),quinazolinyl (e.g., 2-quinazolinyl, 4-quinazolinyl), quinoxalinyl (e.g.,2-quinoxalinyl), benzofuryl (e.g., 2-benzofuryl, 3-benzofuryl),benzothienyl (e.g., 2-benzothienyl, 3-benzothienyl), benzoxazolyl (e.g.,2-benzoxazolyl), benzothiazolyl (e.g., 2-benzothiazolyl,5-benzothiazolyl, 6-benzothiazolyl), benzimidazolyl (e.g.,benzimidazol-1-yl, benzimidazol-2-yl, benzimidazol-5-yl,benzimidazol-6-yl), indolyl (e.g., indol-1-yl, indol-3-yl, indol-4-yl,indol-5-yl, indol-6-yl), indazolyl (e.g., 1H-indazol-3-yl),pyrrolopyrazinyl (e.g., 1H-pyrrolo[2,3-b]pyrazin-2-yl,1H-pyrrolo[2,3-b]pyrazin-6-yl), imidazopyridyl (e.g.,1H-imidazo[4,5-b]pyridin-2-yl, 1H-imidazo[4,5-c]pyridin-2-yl),imidazopyrazinyl (e.g., 1H-imidazo[4,5-b]pyrazin-2-yl), benzisoxazolyl,benzotriazolyl, pyrazolopyridyl, pyrazolothienyl, pyrazolotriazinyl andthe like.

Examples of the non-aromatic cyclic hydrocarbon group includecycloalkyl, cycloalkenyl, cycloalkadienyl and the like, each of which isoptionally fused with benzene ring.

Examples of the non-aromatic cyclic hydrocarbon group specificallyinclude C₃₋₁₀ cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl), C₃₋₁₀cycloalkenyl (e.g., cyclopropenyl, cyclobutenyl, cyclopentenyl,cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, cyclodecenyl),C₄₋₁₀ cycloalkadienyl (e.g., cyclobutadienyl, cyclopentadienyl,cyclohexadienyl, cycloheptadienyl, cyclooctadienyl, cyclononadienyl,cyclodecadienyl), fused ring formed by fusion of these groups andbenzene ring (e.g., indanyl (e.g., 1-indanyl), tetrahydronaphthyl (e.g.,1,2,3,4-tetrahydronaphthalen-1-yl), fluorenyl (e.g., 9-fluorenyl) etc.),and the like.

Examples of the non-aromatic heterocyclic group include 3- to 8-membered(preferably 5- or 6-membered) saturated or unsaturated (preferablysaturated) non-aromatic heterocyclic group and the like.

Examples of the non-aromatic heterocyclic group specifically includeoxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl,tetrahydrofuryl, thiolanyl, piperidinyl, tetrahydropyranyl, thianyl,morpholinyl, thiomorpholinyl, piperazinyl, azepanyl, oxepanyl,thiepanyl, oxazepanyl, thiazepanyl, azocanyl, oxocanyl, thiocanyl,oxazocanyl, thiazocanyl, dioxinyl and the like.

As the “cyclic group” of the “optionally substituted cyclic group” forring Y, aromatic hydrocarbon group, aromatic heterocyclic group arepreferable. As the aromatic hydrocarbon group, C₆₋₁₄ aryl is preferable,C₆₋₁₀ aryl is more preferable, and phenyl is particularly preferable. Asthe aromatic heterocyclic group, monocyclic heterocyclic group or fusedaromatic heterocyclic group is preferable, pyridine ring, or fusedaromatic heterocyclic group formed by fusion of 5-membered monocyclicaromatic heterocyclic group containing, as ring-constituting atom, 1 or2 heteroatoms selected from sulfur atom and nitrogen atom, besidescarbon atoms, and benzene ring (e.g., benzothiazolyl, benzimidazolyl,indolyl etc.) is more preferable, and benzothiazolyl (e.g.,5-benzothiazolyl, 6-benzothiazolyl), benzimidazolyl (e.g.,benzimidazol-5-yl, benzimidazol-6-yl), indolyl (e.g., indol-4-yl,indol-5-yl, indol-6-yl) and the like are particularly preferable.

The “optionally substituted cyclic group” for ring Y may have 1 to theacceptable maximum number of substituents at any substitutablepositions. Where the cyclic group is substituted by two or moresubstituents, the substituents may be the same or different, and it ispreferable to optionally have 1 to 5, more preferably 1 to 3,particularly preferably 1 or 2 substituents.

As the “substituent” of the “optionally substituted cyclic group” forring Y, for example,

(i) halogen atom (e.g., fluorine, chlorine, bromine, iodine),

(ii) cyano,

(iii) nitro,

(iv) optionally substituted hydrocarbon group,

(v) hydroxy,

(vi) optionally substituted hydrocarbon-oxy,

(vii) optionally substituted aminosulfonyl,

(viii) optionally substituted aminocarbonyl,

(ix) acyl,

(x) optionally substituted amino,

(xi) optionally substituted sulfanyl,

(xii) optionally substituted heterocyclic group,

(xiii) optionally substituted heterocyclyl-oxy,

(xiv) oxo,

(xv) optionally substituted sulfinyl,

(xvi) optionally substituted aminothiocarbonyl,

(xvii) optionally esterified carboxy,

and the like (in the present specification, to be referred to asSubstituent Group (1)) can be mentioned.

Hereinafter the substituents listed in Substituent Group (1) areexplained.

As the “optionally substituted hydrocarbon group” in Substituent Group(1)(iv), alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,cycloalkyl-alkyl, cycloalkenyl-alkyl, aryl-alkyl, cycloalkanedienyl andthe like, each of which is optionally substituted, can be mentioned.

In the present specification, examples of the “alkyl” may include linearor branched chain alkyl having 1 to 8, preferably 1 to 6, morepreferably 1 to 4 carbons and the like, specifically methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,isopentyl, tert-pentyl, neopentyl, hexyl, isohexyl, heptyl, octyl andthe like. The “alkyl” may have, for example, at any substitutableposition thereof, 1 to the acceptable maximum number of the substituentsselected from the group of the following substituents (hereinafterabbreviated to as “Substituent Group (2)”):

(1) halogen atom (e.g., fluorine, chlorine, bromine, iodine);

(2) cyano;

(3) nitro;

(4) hydroxy;

(5) C₁₋₆ alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy,isobutoxy, tert-butoxy etc.) optionally substituted by 1 to 3substituents selected from halogen atom (e.g., fluorine, chlorine,bromine, iodine) and C₁₋₆ alkoxy (e.g., methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy, tert-butoxy etc.);(6) C₂₋₆ alkenyloxy (e.g., ethenyloxy, propenyloxy, butenyloxy,pentenyloxy, hexenyloxy etc.) optionally having 1 to 3 halogen atoms(e.g., fluorine, chlorine, bromine, iodine);(7) C₂₋₆ alkynyloxy (e.g., ethynyloxy, propynyloxy, butynyloxy,pentynyloxy, hexynyloxy etc.) optionally having 1 to 3 halogen atoms(e.g., fluorine, chlorine, bromine, iodine);(8) C₃₋₆ cycloalkyl-oxy (e.g., cyclopropyloxy, cyclobutyloxy,cyclopentyloxy, cyclohexyloxy) optionally having 1 to 3 halogen atoms(e.g., fluorine, chlorine, bromine, iodine);(9) C₃₋₆ cycloalkenyloxy (e.g., cyclopropenyloxy, cyclobutenyloxy,cyclopentenyloxy, cyclohexenyloxy etc.) optionally having 1 to 3 halogenatoms (e.g., fluorine, chlorine, bromine, iodine);(10) C₆₋₁₀ aryloxy (e.g., phenyloxy, 1-naphthyloxy, 2-naphthyloxy etc.)optionally having 1 to 3 halogen atoms (e.g., fluorine, chlorine,bromine, iodine);(11) C₃₋₆ cycloalkyl-C₁₋₆ alkoxy (e.g., cyclopropylmethyloxy,cyclopropylethyloxy, cyclobutylmethyloxy, cyclopentylmethyloxy,cyclohexylmethyloxy, cyclohexylethyloxy etc.) optionally having 1 to 3halogen atoms (e.g., fluorine, chlorine, bromine, iodine);(12) C₃₋₆ cycloalkenyl-C₁₋₆ alkoxy (e.g., cyclopentenylmethyloxy,cyclohexenylmethyloxy, cyclohexenylethyloxy, cyclohexenylpropyloxy etc.)optionally having 1 to 3 halogen atoms (e.g., fluorine, chlorine,bromine, iodine);(13) C₆₋₁₀ aryl-C₁₋₆ alkoxy (e.g., phenylmethyloxy, phenylethyloxy etc.)optionally having 1 to 3 halogen atoms (e.g., fluorine, chlorine,bromine, iodine);(14) C₁₋₆ alkyl-aminosulfonyl (e.g., methylaminosulfonyl,ethylaminosulfonyl, propylaminosulfonyl etc.);(15) di-C₁₋₆ alkyl-aminosulfonyl (e.g., dimethylaminosulfonyl,diethylaminosulfonyl, dipropylaminosulfonyl etc.);(16) C₁₋₆ alkyl-aminocarbonyl (e.g., methylaminocarbonyl,ethylaminocarbonyl, propylaminocarbonyl etc.);(17) di-C₁₋₆ alkyl-aminocarbonyl (e.g., dimethylaminocarbonyl,diethylaminocarbonyl, dipropylaminocarbonyl etc.);(18) formyl;(19) C₁₋₆ alkyl-carbonyl (e.g., acetyl, ethylcarbonyl, propylcarbonyl,isopropylcarbonyl etc.);(20) C₂₋₆ alkenyl-carbonyl (e.g., ethenylcarbonyl, propenylcarbonyl,butenylcarbonyl, pentenylcarbonyl, hexenylcarbonyl etc.);(21) C₂₋₆ alkynyl-carbonyl (e.g., ethynylcarbonyl, propynylcarbonyl,butynylcarbonyl, pentynylcarbonyl, hexynylcarbonyl etc.);(22) C₃₋₆ cycloalkyl-carbonyl (e.g., cyclopropylcarbonyl,cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl);(23) C₃₋₆ cycloalkenyl-carbonyl (e.g., cyclopropenylcarbonyl,cyclobutenylcarbonyl, cyclopentenylcarbonyl, cyclohexenylcarbonyl etc.);(24) C₆₋₁₀ aryl-carbonyl (e.g., benzoyl, 1-naphthylcarbonyl,2-naphthylcarbonyl etc.);(25) C₃₋₆ cycloalkyl-C₁₋₆ alkyl-carbonyl (e.g.,cyclopropylmethylcarbonyl, cyclopropylethylcarbonyl,cyclobutylmethylcarbonyl, cyclopentylmethylcarbonyl,cyclohexylmethylcarbonyl, cyclohexylethylcarbonyl etc.);(26) C₃₋₆ cycloalkenyl-C₁₋₆ alkyl-carbonyl (e.g.,cyclopentenylmethylcarbonyl, cyclohexenylmethylcarbonyl,cyclohexenylethylcarbonyl, cyclohexenylpropylcarbonyl etc.);(27) C₆₋₁₀ aryl-C₁₋₆ alkyl-carbonyl (e.g., benzylcarbonyl,phenylethylcarbonyl etc.);(28) 5- or 6-membered monocyclic aromatic heterocyclyl-carbonyl (e.g.,furylcarbonyl, thienylcarbonyl, pyrrolylcarbonyl, oxazolylcarbonyl,isoxazolylcarbonyl, thiazolylcarbonyl, isothiazolylcarbonyl,imidazolylcarbonyl, pyridylcarbonyl, pyrazolylcarbonyl etc.);(29) 8- to 12-membered fused aromatic heterocyclyl-carbonyl (e.g.,benzofurylcarbonyl, isobenzofurylcarbonyl, benzothienylcarbonyl,isobenzothienylcarbonyl, indolylcarbonyl, isoindolylcarbonyl,1H-indazolylcarbonyl, benzimidazolylcarbonyl, benzoxazolylcarbonyletc.);(30) 5- or 6-membered non-aromatic heterocyclyl-carbonyl (e.g.,oxiranylcarbonyl, azetidinylcarbonyl, oxetanylcarbonyl,thietanylcarbonyl, pyrrolidinylcarbonyl, tetrahydrofurylcarbonyl,thiolanylcarbonyl, piperidinylcarbonyl etc.);(31) C₁₋₆ alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl etc.);(32) C₂₋₆ alkenylsulfonyl (e.g., ethenylsulfonyl, propenylsulfonyletc.);(33) C₂₋₆ alkynylsulfonyl (e.g., ethynylsulfonyl, propynylsulfonyl,butynylsulfonyl, pentynylsulfonyl, hexynylsulfonyl etc.);(34) C₃₋₆ cycloalkylsulfonyl (e.g., cyclopropylsulfonyl,cyclobutylsulfonyl etc.);(35) C₃₋₆ cycloalkenylsulfonyl (e.g., cyclopropenylsulfonyl,cyclobutenylsulfonyl etc.);(36) C₆₋₁₀ arylsulfonyl (e.g., phenylsulfonyl etc.);(37) C₃₋₆ cycloalkyl-C₁₋₆ alkyl-sulfonyl (e.g.,cyclopropylmethylsulfonyl etc.);(38) C₃₋₆ cycloalkenyl-C₁₋₆ alkyl-sulfonyl (e.g.,cyclopentenylmethylsulfonyl etc.);(39) C₆₋₁₀ aryl-C₁₋₆ alkyl-sulfonyl (e.g., benzylsulfonyl etc.);(40) 5- or 6-membered monocyclic aromatic heterocyclyl-sulfonyl (e.g.,furylsulfonyl, thienylsulfonyl, pyridylsulfonyl etc.);(41) 8- to 12-membered fused aromatic heterocyclyl-sulfonyl (e.g.,benzofurylsulfonyl, isobenzofurylsulfonyl etc.);(42) 5- or 6-membered non-aromatic heterocyclyl-sulfonyl (e.g.,oxiranylsulfonyl, azetidinylsulfonyl etc.);(43) amino;(44) mono-C₁₋₆ alkylamino (e.g., methylamino, ethylamino, propylamino,isopropylamino, butylamino, isobutylamino, tert-butylamino etc.);(45) di-C₁₋₆ alkylamino (e.g., dimethylamino, diethylamino,dipropylamino, diisopropylamino, dibutylamino, diisobutylamino,di-tert-butylamino etc.);(46) mono-(C₁₋₆ alkyl-carbonyl)amino (e.g., acetylamino,ethylcarbonylamino, propylcarbonylamino, tert-butylcarbonylamino etc.)optionally having 1 to 3 halogen atoms (e.g., fluorine, chlorine,bromine, iodine);(47) mono-(C₃₋₆ cycloalkyl-carbonyl)amino (e.g.,cyclopropylcarbonylamino, cyclobutylcarbonylamino,cyclopentylcarbonylamino, cyclohexylcarbonylamino etc.);(48) mono-(C₆₋₁₀ aryl-carbonyl)amino (e.g., benzoylamino etc.)optionally having 1 to 3 halogen atoms (e.g., fluorine, chlorine,bromine, iodine);(49) mono-(5- or 6-membered monocyclic aromaticheterocyclyl-carbonyl)amino (e.g., furylcarbonylamino,thienylcarbonylamino, pyrrolylcarbonylamino, oxazolylcarbonylamino,isoxazolylcarbonylamino, thiazolylcarbonylamino,isothiazolylcarbonylamino, imidazolylcarbonylamino,pyridylcarbonylamino, pyrazolylcarbonylamino etc.);(50) mono-(8- to 12-membered fused aromatic heterocyclyl-carbonyl)amino(e.g., benzofurylcarbonylamino, isobenzofurylcarbonylamino,benzothienylcarbonylamino, isobenzothienylcarbonylamino etc.);(51) mono-(5- or 6-membered non-aromatic heterocyclyl-carbonyl)amino(e.g., oxiranylcarbonylamino, azetidinylcarbonylamino,oxetanylcarbonylamino etc.);(52) thiol;(53) C₁₋₆ alkylsulfanyl (e.g., methylsulfanyl, ethylsulfanyl etc.);(54) C₂₋₆ alkenylsulfanyl (e.g., ethenylsulfanyl, propenylsulfanyletc.);(55) C₂₋₆ alkynylsulfanyl (e.g., ethynylsulfanyl, propynylsulfanyl,butynylsulfanyl, pentynylsulfanyl, hexynylsulfanyl etc.);(56) C₃₋₆ cycloalkylsulfanyl (e.g., cyclopropylsulfanyl,cyclobutylsulfanyl etc.);(57) C₃₋₆ cycloalkenylsulfanyl (e.g., cyclopropenylsulfanyl,cyclobutenylsulfanyl etc.);(58) C₆₋₁₀ arylsulfanyl (e.g., phenylsulfanyl etc.);(59) C₃₋₆ cycloalkyl-C₁₋₆ alkyl-sulfanyl (e.g.,cyclopropylmethylsulfanyl etc.);(60) C₃₋₆ cycloalkenyl-C₁₋₆ alkyl-sulfanyl (e.g.,cyclopentenylmethylsulfanyl etc.);(61) 5- or 6-membered monocyclic aromatic heterocyclic group (e.g.,furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,imidazolyl, pyridyl, pyrazolyl etc.) optionally having 1 to 3 C₁₋₄ alkyl(e.g., methyl, ethyl etc.);(62) 8- to 12-membered fused aromatic heterocyclic group (e.g.,benzofuryl, isobenzofuryl, benzothienyl, isobenzothienyl, indolyl,isoindolyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl etc.);(63) 5- or 6-membered non-aromatic heterocyclic group (e.g., oxiranyl,azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl,thiolanyl, piperidinyl etc.);(64) 5- or 6-membered monocyclic aromatic heterocyclyl-oxy (e.g.,furyloxy, thienyloxy, pyrrolyloxy, oxazolyloxy, isoxazolyloxy,thiazolyloxy, isothiazolyloxy, imidazolyloxy, pyridyloxy, pyrazolyloxyetc.);(65) 8- to 12-membered fused aromatic heterocyclyl-oxy (e.g.,benzofuryloxy, isobenzofuryloxy, benzothienyloxy, isobenzothienyloxy,indolyloxy, isoindolyloxy, 1H-indazolyloxy, benzimidazolyloxy,benzoxazolyloxy etc.);(66) 5- or 6-membered non-aromatic heterocyclyl-oxy (e.g., oxiranyloxy,azetidinyloxy, oxetanyloxy, thietanyloxy, pyrrolidinyloxy,tetrahydrofuryloxy, thiolanyloxy, piperidinyloxy etc.);(67) oxo;(68) C₁₋₆ alkylsulfinyl (e.g., methylsulfinyl, ethylsulfinyl etc.);(69) C₂₋₆ alkenylsulfinyl (e.g., ethenylsulfinyl, propenylsulfinyletc.);(70) C₂₋₆ alkynylsulfinyl (e.g., ethynylsulfinyl, propynylsulfinyl,butynylsulfinyl, pentynylsulfinyl, hexynylsulfinyl etc.);(71) C₃₋₆ cycloalkylsulfinyl (e.g., cyclopropylsulfinyl,cyclobutylsulfinyl etc.);(72) C₃₋₆ cycloalkenylsulfinyl (e.g., cyclopropenylsulfinyl,cyclobutenylsulfinyl etc.);(73) C₆₋₁₀ arylsulfinyl (e.g., phenylsulfinyl etc.);(74) C₃₋₆ cycloalkyl-C₁₋₆ alkyl-sulfinyl (e.g.,cyclopropylmethylsulfinyl etc.);(75) C₃₋₆ cycloalkenyl-C₁₋₆ alkyl-sulfinyl (e.g.,cyclopentenylmethylsulfinyl etc.);(76) aminothiocarbonyl substituted by C₁₋₆ alkyl or C₆₋₁₀ aryl-C₁₋₄alkyl-carbonyl (e.g., methylaminothiocarbonyl, ethylaminothiocarbonyl,propylaminothiocarbonyl, benzylcarbonylaminothiocarbonyl etc.);(77) di-C₁₋₆ alkyl-aminothiocarbonyl (e.g., dimethylaminothiocarbonyl,diethylaminothiocarbonyl, dipropylaminothiocarbonyl etc.);(78) carboxy;(79) C₁₋₆ alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,tert-butoxycarbonyl etc.);(80) C₂₋₆ alkenyloxy-carbonyl (e.g., ethenyloxycarbonyl,propenyloxycarbonyl, butenyloxycarbonyl, pentenyloxycarbonyl,hexenyloxycarbonyl etc.);(81) C₂₋₆ alkynyloxy-carbonyl (e.g., ethynyloxycarbonyl,propynyloxycarbonyl, butynyloxycarbonyl, pentynyloxycarbonyl,hexynyloxycarbonyl etc.);(82) C₃₋₆ cycloalkyl-oxy-carbonyl (e.g., cyclopropyloxycarbonyl,cyclobutyloxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyletc.);(83) C₃₋₆ cycloalkenylcxy-carbonyl (e.g., cyclopropenyloxycarbonyl,cyclobutenyloxycarbonyl, cyclopentenyloxycarbonyl,cyclohexenyloxycarbonyl etc.);(84) C₆₋₁₀ aryloxy-carbonyl (e.g., phenyloxycarbonyl,1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl etc.);(85) C₃₋₆ cycloalkyl-C₁₋₆ alkoxy-carbonyl (e.g.,cyclopropylmethyloxycarbonyl, cyclopropylethyloxycarbonyl,cyclobutylmethyloxycarbonyl, cyclopentylmethyloxycarbonyl,cyclohexylmethyloxycarbonyl, cyclohexylethyloxycarbonyl etc.);(86) C₃₋₆ cycloalkenyl-C₁₋₆ alkoxy-carbonyl (e.g.,cyclopentenylmethyloxycarbonyl, cyclohexenylmethyloxycarbonyl,cyclohexenylethyloxycarbonyl, cyclohexenylpropyloxycarbonyl etc.); and(87) C₆₋₁₀ aryl-C₁₋₆ alkoxy-carbonyl (e.g., phenylmethyloxycarbonyl,phenylethyloxycarbonyl etc.).

Where the alkyl is substituted by two or more substituents, thesubstituents may be the same or different, and preferable number of thesubstituents is 1 to 5, and more preferably 1 to 3.

As the “alkenyl”, for example, linear or branched chain alkenyl having 2to 8, preferably 2 to 4 carbons and the like can be mentioned, andethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl,butadienyl and the like can be specifically mentioned. The “alkenyl” mayhave, at any substitutable positions, 1 to the acceptable maximum numberof substituents selected from the above-mentioned Substituent Group (2)and C₆₋₁₀ aryl (e.g., phenyl etc.). Where the alkenyl is substituted bytwo or more substituents, the substituents may be the same or different,and preferable number of the substituents is 1 to 5, more preferably 1to 3.

As the “alkynyl”, for example, linear or branched chain alkynyl having 2to 8, preferably 2 to 4 carbons and the like can be mentioned, andethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl and thelike can be specifically mentioned. The “alkynyl” may have, at anysubstitutable positions, 1 to the acceptable maximum number ofsubstituents selected from the above-mentioned Substituent Group (2) andC₆₋₁₀ aryl (e.g., phenyl etc.). Where the alkynyl is substituted by twoor more substituents, the substituents may be the same or different, andpreferable number of the substituents is 1 to 5, more preferably 1 to 3.

As the “cycloalkyl”, for example, cycloalkyl having 3 to 8, preferably 3to 6 carbons and the like can be mentioned, and cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl and the like can bespecifically mentioned. The “cycloalkyl” may have, at any substitutablepositions, 1 to the acceptable maximum number of substituents selectedfrom (a) C₁₋₆ alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl,isobutyl, tert-butyl etc.) optionally having 1 to 3 substituentsselected from halogen atom (e.g., fluorine, chlorine, bromine, iodine)and hydroxy, and (b) substituent selected from the above-mentionedSubstituent Group (2). Where the cycloalkyl is substituted by two ormore substituents, the substituents may be the same or different, andpreferable number of the substituents is 1 to 5, more preferably 1 to 3.

As the “cycloalkenyl”, for example, cycloalkenyl having 3 to 8,preferably 3 to 6 carbons and the like can be mentioned, andcyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl,cyclooctenyl and the like can be specifically mentioned. The“cycloalkenyl” may have, at any substitutable positions, 1 to theacceptable maximum number of substituents selected from C₁₋₆ alkyl(e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyletc.) optionally having 1 to 3 halogen atoms (e.g., fluorine, chlorine,bromine, iodine), and substituent selected from the above-mentionedSubstituent Group (2). Where the cycloalkenyl is substituted by two ormore substituents, the substituents may be the same or different, andpreferable number of the substituents is 1 to 5, more preferably 1 to 3.

As the “aryl”, for example, aryl having 6 to 18, preferably 6 to 14,more preferably 6 to 10, particularly preferably 6 carbons and the likecan be mentioned, and phenyl, 1-naphthyl, 2-naphthyl, biphenylyl,2-anthryl, phenanthryl, acenaphthylenyl and the like can be specificallymentioned. The “aryl” may have, at any substitutable positions, 1 to theacceptable maximum number of substituents selected from (a) C₁₋₄ alkyl(e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyletc.) optionally having 1 to 3 substituents selected from halogen atom(e.g., fluorine, chlorine, bromine, iodine), cyano, hydroxy and C₃₋₆cycloalkyl (e.g., cyclopropyl etc.), and (b) substituent selected fromthe above-mentioned Substituent Group (2) (except for oxo). Where thearyl is substituted by two or more substituents, the substituents may bethe same or different, and preferable number of the substituents is 1 to5, more preferably 1 to 3.

As the “cycloalkyl-alkyl”, for example, group in which cycloalkyl grouphaving 3 to 8, preferably 3 to 6 carbons and the like, is bonded tolinear or branched chain alkyl having 1 to 6, preferably 1 to 4 carbonatoms (e.g., C₃₋₈ cycloalkyl-C₁₋₄ alkyl) and the like can be mentioned,and cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl,cyclopentylmethyl, cyclohexylmethyl, cyclohexylethyl and the like can bespecifically mentioned. The “cycloalkyl-alkyl” may have, at anysubstitutable positions, 1 to the acceptable maximum number ofsubstituents selected from C₁₋₆ alkyl (e.g., methyl, ethyl, propyl,isopropyl, butyl, isobutyl, tert-butyl etc.) optionally having 1 to 3halogen atoms (e.g., fluorine, chlorine, bromine, iodine) andsubstituent selected from the above-mentioned Substituent Group (2).Where the cycloalkyl-alkyl is substituted by two or more substituents,the substituents may be the same or different, and preferable number ofthe substituents is 1 to 5, more preferably 1 to 3.

As the “cycloalkenyl-alkyl”, for example, group in which cycloalkenylhaving 3 to 8, preferably 3 to 6 carbons is bonded to linear or branchedchain alkyl having 1 to 6, preferably 1 to 4 carbon atoms (e.g., C₃₋₈cycloalkenyl-C₁₋₄ alkyl group) can be mentioned, andcyclopentenylmethyl, cyclohexenylmethyl, cyclohexenylethyl,cyclohexenylpropyl, cycloheptenylmethyl, cycloheptenylethyl and the likecan be specifically mentioned. The “cycloalkenyl-alkyl” may have, at anysubstitutable positions, 1 to the acceptable maximum number ofsubstituents selected from C₁₋₆ alkyl (e.g., methyl, ethyl, propyl,isopropyl, butyl, isobutyl, tert-butyl etc.) optionally having 1 to 3halogen atoms (e.g., fluorine, chlorine, bromine, iodine) andsubstituent selected from the above-mentioned Substituent Group (2).Where the cycloalkenyl-alkyl is substituted by two or more substituents,the substituents may be the same or different, and preferable number ofthe substituents is 1 to 5, more preferably 1 to 3.

As the “aryl-alkyl”, for example, group in which aryl having 6 to 18,more preferably 6 to 10, particularly preferably 6 carbons is bonded tolinear or branched chain alkyl having 1 to 6, preferably 1 to 4 carbonatoms (e.g., C₆₋₁₈ aryl-C₁₋₄ alkyl) and the like can be mentioned, andphenylmethyl (benzyl), phenylethyl (phenethyl) and the like can bespecifically mentioned. The “aryl-alkyl” may have, at any substitutablepositions, 1 to the acceptable maximum number of substituents selectedfrom C₁₋₆ alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl,isobutyl, tert-butyl etc.) optionally having 1 to 3 halogen atoms (e.g.,fluorine, chlorine, bromine, iodine) and substituent selected from theabove-mentioned Substituent Group (2). Where the aryl-alkyl issubstituted by two or more substituents, the substituents may be thesame or different, and preferable number of the substituents is 1 to 5,more preferably 1 to 3.

As the “cycloalkanedienyl”, for example, C₄₋₆ cycloalkanedienyl groupsuch as 2,4-cyclopentadien-1-yl, 2,4-cyclohexadien-1-yl,2,5-cyclohexadien-1-yl and the like, and the like can be mentioned. The“cycloalkanedienyl” may have, at any substitutable positions, 1 to theacceptable maximum number of substituents selected from C₁₋₆ alkyl(e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyletc.) optionally having 1 to 3 halogen atoms (e.g., fluorine, chlorine,bromine, iodine) and substituent selected from the above-mentionedSubstituent Group (2). Where the cycloalkanedienyl is substituted by twoor more substituents, the substituents may be the same or different, andpreferable number of the substituents is 1 to 5, more preferably 1 to 3.

As the “optionally substituted hydrocarbon-oxy” in Substituent Group(1)(vi), alkyl-oxy, alkenyl-oxy, alkynyl-oxy, cycloalkyl-oxy,cycloalkenyl-oxy, aryl-oxy, cycloalkyl-alkyl-oxy,cycloalkenyl-alkyl-oxy, aryl-alkyl-oxy and the like, each of which isoptionally substituted, can be mentioned. As the “alkyl” for alkyl-oxy,the “alkenyl” for alkenyl-oxy, the “alkynyl” for alkynyl-oxy, the“cycloalkyl” for cycloalkyl-oxy, the “cycloalkenyl” forcycloalkenyl-oxy, the “aryl” for aryl-oxy, the “cycloalkyl-alkyl” forcycloalkyl-alkyl-oxy, the “cycloalkenyl-alkyl” forcycloalkenyl-alkyl-oxy, the “aryl-alkyl” for aryl-alkyl-oxy, similargroups to those exemplified as the “hydrocarbon group” of the“optionally substituted hydrocarbon group” in the aforementionedSubstituent Group (1)(iv) can be respectively mentioned.

The “optionally substituted aminosulfonyl” in Substituent Group (1)(vii) may have 1 or 2 substituents. Where the aminosulfonyl issubstituted by two substituents, the substituents may be the same ordifferent.

As the “substituent” of the “optionally substituted aminosulfonyl”, forexample, similar groups to those exemplified as the “hydrocarbon group”of the “optionally substituted hydrocarbon group” in the aforementionedSubstituent Group (1)(iv) and the below-mentioned groups as the“optionally substituted heterocyclic group” in the aforementionedSubstituent Group (1)(xii) can be mentioned.

The “optionally substituted aminocarbonyl” in Substituent Group (1)(viii) may have 1 or 2 substituents. Where the aminocarbonyl issubstituted by two substituents, the substituents may be the same ordifferent.

As the “substituent” of the “optionally substituted aminocarbonyl”, forexample, those similar to group exemplified as the “optionallysubstituted hydrocarbon group” in the aforementioned Substituent Group(1)(iv), group exemplified as the “optionally substitutedhydrocarbon-oxy” in the aforementioned Substituent Group (1)(vi), andgroup below-mentioned as “optionally substituted heterocycle” in theaforementioned Substituent Group (1)(xii) can be mentioned.

As the “acyl” in Substituent Group (1)(ix), for example, optionallysubstituted hydrocarbon-carbonyl, optionally substitutedheterocyclyl-carbonyl, optionally substituted hydrocarbon-sulfonyl,optionally substituted heterocyclyl-sulfonyl and the like can bementioned.

As the “optionally substituted hydrocarbon” of the “optionallysubstituted hydrocarbon-carbonyl”, those similar to the groupexemplified as the “optionally substituted hydrocarbon group” in theabove-mentioned Substituent Group (1)(iv) can be mentioned.

As the “optionally substituted hydrocarbon” of the “optionallysubstituted hydrocarbon-sulfonyl”, those similar to the groupexemplified as the “optionally substituted hydrocarbon group” in theabove-mentioned Substituent Group (1)(iv) can be mentioned.

As the “optionally substituted heterocycle” of the “optionallysubstituted heterocyclyl-carbonyl” and “optionally substitutedheterocyclyl-sulfonyl”, those similar to the group below-mentioned asthe “optionally substituted heterocyclic group” in the aforementionedSubstituent Group (1)(xii) can be mentioned.

The “optionally substituted amino” in Substituent Group (1)(x) may have1 or 2 substituents. Where the amino is substituted by two substituents,the substituents may be the same or different. As the “substituent” ofthe “optionally substituted amino”, for example, those similar to thegroup exemplified as the “optionally substituted hydrocarbon group” inthe aforementioned Substituent Group (1)(iv), the group exemplified asthe “optionally substituted aminocarbonyl” in the aforementionedSubstituent Group (1)(viii), the group exemplified as the “acyl” in theaforementioned Substituent Group (1)(ix), the group below-mentioned asthe “optionally substituted heterocyclic group” in the aforementionedSubstituent Group (1)(xii), and group selected from the “optionallyesterified carboxy” in the aforementioned Substituent Group (1)(xviii)can be mentioned.

As the “substituent” of the “optionally substituted sulfanyl” inSubstituent Group (1)(xi), for example, those similar to the groupexemplified as the “optionally substituted hydrocarbon group” in theaforementioned Substituent Group (1)(iv) can be mentioned.

As the “heterocyclic group” of the “optionally substituted heterocyclicgroup” in Substituent Group (1)(xii), aromatic heterocyclic group (e.g.,monocyclic aromatic heterocyclic group, fused aromatic heterocyclicgroup), non-aromatic heterocyclic group, and the like can be mentioned,and for example, 5- to 12-membered aromatic heterocyclic group(monocyclic aromatic heterocyclic group or fused aromatic heterocyclicgroup etc.), saturated or unsaturated non-aromatic heterocycle, and thelike having, as ring-constituting atom, 1 or more (preferably 1 to 4,more preferably 1 or 2) of 1 to 3, preferably 1 or 2 kinds ofheteroatoms selected from oxygen atom, optionally oxidized sulfur atomand nitrogen atom and the like (preferably oxygen atom, sulfur atom andnitrogen atom etc.) besides carbon atoms, can be mentioned.

As the monocyclic aromatic heterocyclic group, for example, 5- or6-membered monocyclic aromatic heterocyclic group and the like can bementioned.

As the monocyclic aromatic heterocyclic group, furyl, thienyl, pyrrolyl,oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl,oxadiazolyl (e.g., 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,1,3,4-oxadiazolyl), furazanyl, thiadiazolyl (e.g., 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl), triazolyl (e.g.,1,2,3-triazolyl, 1,2,4-triazolyl), tetrazolyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, triazinyl and the like can be specificallymentioned.

As the fused aromatic heterocyclic group, for example, 8- to 12-memberedfused aromatic heterocyclic group can be mentioned, and heterocyclicgroup formed by fusion of the aforementioned 5- or 6-membered monocyclicaromatic heterocyclic group and benzene ring or heterocyclic groupformed by fusion of the same or different two of the aforementioned 5-or 6-membered monocyclic aromatic heterocyclic groups can beparticularly mentioned.

Examples of fused aromatic heterocyclic group specifically includebenzofuryl, isobenzofuryl, benzothienyl, isobenzothienyl, indolyl,isoindolyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl,1,2-benzisoxazolyl, benzothiazolyl, 1,2-benzoisothiazolyl,1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl,quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl,carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acrydinyl,phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathiinyl, thianthrenyl,phenanthridinyl, phenanthrolinyl, indolizinyl,pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridyl,imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridazinyl,imidazo[1,2-a]pyrimidinyl, 1,2,4-triazolo[4,3-a]pyridyl,1,2,4-triazolo[4,3-b]pyridazinyl and the like.

Examples of non-aromatic heterocyclic group include 3- to 8-membered(preferably 5- or 6-membered) saturated or unsaturated (preferablysaturated) non-aromatic heterocyclic group and the like.

Examples of non-aromatic heterocyclic group specifically includeoxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl,tetrahydrofuryl, thiolanyl, piperidinyl, tetrahydropyranyl, thianyl,morpholinyl, thiomorpholinyl, piperazinyl, azepanyl, oxepanyl,thiepanyl, oxazepanyl, thiazepanyl, azocanyl, oxocanyl, thiocanyl,oxazocanyl, thiazocanyl, dioxinyl and the like.

Alternatively, the non-aromatic heterocyclic group may be fused tobenzene ring or the above-mentioned monocyclic aromatic heterocyclicgroup to form fused non-aromatic heterocyclic group. As the fusednon-aromatic heterocyclic group formed by fusion of non-aromaticheterocyclic group and benzene ring, for example, benzodioxinyl,tetrahydroisoquinolyl and the like can be mentioned.

The “optionally substituted heterocyclic group” may have, at anysubstitutable positions, 1 to the acceptable maximum number ofsubstituents. Where the heterocyclic group is substituted by two or moresubstituents, the substituents may be the same or different, andpreferable number of the substituents is 1 to 5, more preferably 1 to 3.

Examples of the “substituent” of the “optionally substitutedheterocyclic group” may include (a) C₁₋₆ alkyl (e.g., methyl, ethyl,propyl, isopropyl, butyl, isobutyl, tert-butyl etc.) optionally having 1to 3 substituents selected from halogen atom (e.g., fluorine, chlorine,bromine, iodine), cyano, hydroxy and C₁₋₄ alkoxy (e.g., methoxy), (b)C₆₋₁₀ aryl (e.g., phenyl), (c) C₆₋₁₀ aryl-C₁₋₄ alkyl (e.g., benzyl etc.)and (d) those similar to the group selected from the aforementionedSubstituent Group (2).

For example, among the heterocyclic groups substituted by oxo in theaforementioned Substituent Group (2), as the specific examples of thenon-aromatic heterocyclic group substituted by oxo, 2-oxoazetidinyl,2-oxopyrrolidinyl, 2-oxopiperidinyl, 2-oxoazepanyl, 2-oxoazocanyl,2-oxotetrahydrofuryl, 2-oxotetrahydropyranyl, 2-oxothiolanyl,2-oxothianyl, 2-oxopiperazinyl, 2-oxooxepanyl, 2-oxooxazepanyl,2-oxothiepanyl, 2-oxothiazepanyl, 2-oxooxocanyl, 2-oxothiocanyl,2-oxooxazocanyl, 2-oxothiazocanyl, 2-oxodioxinyl and the like can bementioned.

As the “optionally substituted heterocycle” of the “optionallysubstituted heterocyclyl-oxy” in Substituent Group (1)(xiii), thosesimilar to the group exemplified as the “optionally substitutedheterocycle” in the aforementioned Substituent Group (1)(xii) can bementioned.

As the “substituent” of the “optionally substituted sulfinyl” inSubstituent Group (1)(xv), for example, those similar to the groupexemplified as the “optionally substituted hydrocarbon group” in theaforementioned Substituent Group (1)(iv) can be mentioned.

The “optionally substituted aminothiocarbonyl” in Substituent Group (1)(xvi) may have 1 or 2 substituents. Where the aminothiocarbonyl issubstituted by 2 substituents, the substituents may be the same ordifferent.

As the “substituent” of the “optionally substituted aminothiocarbonyl”,for example, 1 or 2 groups similar to the group exemplified as the“optionally substituted hydrocarbon group” in the aforementionedSubstituent Group (1)(iv) can be mentioned.

As the “optionally esterified carboxy” in Substituent Group (1)(xvii),for example, carboxy optionally esterified by the group exemplified asthe “optionally substituted hydrocarbon group” in the aforementionedSubstituent Group (1)(iv) can be mentioned.

The “substituent” of the “optionally substituted cyclic group” for ringY is preferably

(1) halogen atom (e.g., fluorine, chlorine, bromine, iodine),

(2) optionally substituted alkyl,

(3) optionally substituted alkoxy,

(4) optionally substituted aminocarbonyl,

(5) optionally substituted amino,

(6) optionally esterified carboxy,

(7) nitro,

and the like.

Of these,

(1) halogen atom (e.g., fluorine, chlorine, bromine, iodine),

(2) optionally substituted alkyl,

(3) optionally substituted amino,

and the like are preferable.

Hereinafter the above-mentioned preferable examples of the “substituent”of the “optionally substituted cyclic group” for ring Y are exemplifiedin detail.

(1) As the halogen atom, fluorine, chlorine, bromine and the like arepreferable.

(2) As the optionally substituted alkyl, optionally substituted C₁₋₈alkyl is preferable, optionally substituted C₁₋₄ alkyl is morepreferable, and unsubstituted C₁₋₄ alkyl is much more preferable.Specifically, methyl, ethyl and the like are preferable.

(3) As the optionally substituted alkoxy, optionally substituted C₁₋₈alkoxy is preferable, optionally substituted C₁₋₄ alkoxy is morepreferable, unsubstituted C₁₋₄ alkoxy is much more preferable.Specifically, methoxy and the like are preferable.

(4) As the “substituent” for the optionally substituted aminocarbonyl,for example, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₈ cycloalkyl,C₃₋₈ cycloalkenyl, C₃₋₈ cycloalkynyl, C₆₋₁₈ aryl, heterocyclic group andthe like, each of which is optionally substituted, are preferable. Ofthese, optionally substituted C₁₋₄ alkyl, optionally substituted C₆₋₁₂aryl and optionally substituted 5-membered heterocyclic group and thelike are preferable. Particularly, (a) C₁₋₄ alkyl (e.g., methyl, ethyl)optionally having C₆₋₁₂ aryl (e.g., phenyl) (Specific examples arebenzyl, ethyl), (b) 5-membered heterocyclic group (e.g., pyrazolyl)optionally substituted by 1 to 3 substituents selected from C₁₋₄ alkyl(e.g., methyl) and C₆₋₁₂ aryl (e.g., phenyl), (c) C₆₋₁₂ aryl optionallysubstituted by C₁₋₄ alkyl (e.g., methyl) optionally substituted by 1 to3 substituents selected from halogen atom (e.g., fluorine) and cyano(specific examples: trifluoromethyl, tert-butyl, 1-cyano-1-methylethyl)are preferable.(5) As the “substituent” for the optionally substituted amino,optionally substituted alkyl, optionally substituted aminocarbonyl,acyl, optionally substituted aminothiocarbonyl and the like arepreferable.

As the optionally substituted amino, amino optionally substituted by 1or 2 substituents selected from (a) optionally substituted alkyl, (b)optionally substituted aminocarbonyl, (c) acyl and (d) optionallysubstituted aminothiocarbonyl is preferable.

As the optionally substituted alkyl, optionally substituted C₁₋₄ alkylis preferable. Of these, C₁₋₄ alkyl (e.g., methyl) optionallysubstituted by 5-membered heterocyclic group (e.g., pyrazolyl)optionally substituted by 1 to 3 C₁₋₄ alkyl (e.g., methyl) (specificexample: 1,3-dimethyl-1H-pyrazol-5-ylmethyl) is preferable.

As the optionally substituted aminocarbonyl, C₁₋₈ alkyl-aminocarbonyl,C₆₋₁₈ aryl-aminocarbonyl, C₆₋₁₈ aryl-C₁₋₄ alkyl-aminocarbonyl,heterocyclyl-aminocarbonyl, C₃₋₈ cycloalkyl-aminocarbonyl, C₁₋₈alkoxy-aminocarbonyl and the like, each of which is optionallysubstituted, are preferable. Of these, optionally substituted C₁₋₈alkyl-aminocarbonyl, optionally substituted C₆₋₁₈ aryl-aminocarbonyl,optionally substituted heterocyclyl-aminocarbonyl, optionallysubstituted C₁₋₈ alkoxy-aminocarbonyl and the like are preferable.Particularly, (i) C₁₋₄ alkyl-aminocarbonyl (e.g., ethylaminocarbonyl),(ii) C₆₋₁₀ aryl-aminocarbonyl (e.g., phenylaminocarbonyl) optionallysubstituted by C₁₋₄ alkyl (e.g., methyl) optionally substituted by 1 to3 halogen atom (e.g., fluorine) (specific examples: phenylaminocarbonyl,3-(trifluoromethyl)phenylcarbonyl), (iii) C₁₋₄ alkoxy-aminocarbonyl(e.g., methoxyaminocarbonyl, isobutoxyaminocarbonyl), (iv) 5-memberedheterocyclyl-aminocarbonyl (e.g., pyrazolyl) optionally substituted by 1to 3 substituents selected from C₁₋₄ alkyl (e.g., methyl) and C₆₋₁₀ aryl(specific example: 1,3-dimethyl-1H-pyrazol-5-yl-aminocarbonyl) and thelike are preferable.

As the acyl, C₁₋₈ alkyl-carbonyl, C₂₋₈ alkenyl-carbonyl, C₂₋₈alkynyl-carbonyl, C₃₋₈ cycloalkyl-carbonyl, C₃₋₈ cycloalkenyl-carbonyl,C₆₋₁₈ aryl-carbonyl, C₆₋₁₈ aryl-C₁₋₄ alkyl-carbonyl, C₁₋₈ alkylsulfonyl,C₆₋₁₈ aryl-sulfonyl, heterocyclyl-carbonyl, heterocyclyl-sulfonyl andthe like, each of which is optionally substituted, are preferable. Ofthese, C₁₋₈ alkyl-carbonyl, C₂₋₈ alkenyl-carbonyl, C₂₋₈alkynyl-carbonyl, C₃₋₈ cycloalkyl-carbonyl, C₃₋₈ cycloalkenyl-carbonyl,C₆₋₁₈ aryl-carbonyl, heterocyclyl-carbonyl, each of which is optionallysubstituted, are preferable.

As the optionally substituted C₁₋₈ alkyl-carbonyl, optionallysubstituted C₁₋₄ alkyl-carbonyl is preferable. Particularly, C₁₋₄alkyl-carbonyl (e.g., methylcarbonyl, tert-butylcarbonyl,3-methylbutanoyl) optionally substituted by 1 to 3 substituents selectedfrom (a) hydroxy, (b) C₁₋₄ alkylsulfonyl (e.g., methylsulfonyl) and (c)6-membered heterocyclic group (e.g., pyridyl) (specific examples:methylsulfonylmethylcarbonyl, 2-pyridylmethylcarbonyl,tert-butylcarbonyl, 3-hydroxy-3-methylbutanoyl) is preferable.

As the optionally substituted C₂₋₈ alkenyl-carbonyl, optionallysubstituted C₂₋₄ alkenyl-carbonyl is preferable. Particularly, C₂₋₄alkenyl-carbonyl (e.g., 3-methyl-2-butenoyl) optionally substituted byC₆₋₁₀ aryl (e.g., phenyl) (specific example: 3-methyl-2-butenoyl) ispreferable.

As the optionally substituted C₂₋₈ alkynyl-carbonyl, optionallysubstituted C₂₋₄ alkynyl-carbonyl is preferable. Particularly, C₂₋₄alkynyl-carbonyl (e.g., 2-butynoyl) optionally substituted by C₆₋₁₀ aryl(e.g., phenyl) (specific example: 2-butynoyl) is preferable.

As the optionally substituted C₃₋₈ cycloalkyl-carbonyl, C₃₋₆cycloalkyl-carbonyl is preferable, and cyclopropylcarbonyl,cyclopentylcarbonyl and cyclohexylcarbonyl are specifically preferable.

As the optionally substituted C₃₋₈ cycloalkenyl-carbonyl, C₃₋₆cycloalkenyl-carbonyl (e.g., cyclopentenecarbonyl) (specific example:1-cyclopentenecarbonyl) is preferable.

As the optionally substituted C₆₋₁₈ aryl-carbonyl, optionallysubstituted C₆₋₁₀ aryl-carbonyl is preferable. Particularly, C₆₋₁₀aryl-carbonyl (e.g., benzoyl) optionally substituted by 1 to 3substituents selected from (a) halogen atom (e.g., fluorine), (b) C₁₋₄alkyl (e.g., methyl, ethyl, isopropyl, tert-butyl) optionallysubstituted by 1 to 3 substituents selected from halogen atom (e.g.,fluorine), cyano, hydroxy and C₃₋₆ cycloalkyl (e.g., cyclopropyl)(specific example: trifluoromethyl), (c) C₃₋₆ cycloalkyl (e.g.,cyclopropyl, cyclobutyl, cyclohexyl) optionally substituted by cyano,(d) C₁₋₄ alkoxy (e.g., isopropoxy, tert-butoxy) optionally substitutedby 1 to 5 halogen atoms (e.g., fluorine), (e) C₁₋₄ alkoxy-carbonyl(e.g., methoxycarbonyl), and (f) 5 or 6-membered heterocyclic group(e.g., tetrahydropyranyl, pyrrolidinyl) optionally substituted by cyanoor oxo is preferable. Specifically, phenylcarbonyl (benzoyl),3-(trifluoromethyl)phenylcarbonyl, 4-(trifluoromethyl)phenylcarbonyl,3-fluorophenylcarbonyl, 3-chlorophenylcarbonyl,3-(1-cyanocyclopropyl)phenylcarbonyl,3-(1-cyanocyclobutyl)phenylcarbonyl,3-(1-cyanocyclohexyl)phenylcarbonyl,2-fluoro-3-(trifluoromethyl)phenylcarbonyl,2-fluoro-5-(trifluoromethyl)phenylcarbonyl,3-fluoro-5-(trifluoromethyl)phenylcarbonyl,4-chloro-3-(trifluoromethyl)phenylcarbonyl,2-chloro-3-(trifluoromethyl)phenylcarbonyl,2-chloro-5-(trifluoromethyl)phenylcarbonyl, 3-isopropoxyphenylcarbonyl,3-(tert-butoxy)phenylcarbonyl, 3-(1-cyano-1-methylethyl)phenylcarbonyl,3-methoxyphenylcarbonyl, 3-methoxycarbonylphenylcarbonyl,3-(trifluoromethoxy)carbonylphenylcarbonyl,3-(1,1,2,2-tetrafluoroethoxy)phenylcarbonyl,3-(4-cyanotetrahydropyran-4-yl)phenylcarbonyl,3,5-di(trifluoromethyl)phenylcarbonyl,3-(2-oxopyrrolidin-1-yl)phenylcarbonyl, 4-(tert-butyl)phenylcarbonyl,3-(1-cyanoethyl)phenylcarbonyl,3-(1-cyano-2-cyclopropyl-1-methylethyl)phenylcarbonyl and the like arepreferable.

As the optionally substituted C₆₋₁₈ aryl-C₁₋₄ alkyl-carbonyl, C₆₋₁₀aryl-C₁₋₄ alkyl-carbonyl is preferable.

As the optionally substituted C₁₋₈ alkylsulfonyl, C₁₋₄ alkylsulfonyl arepreferable.

As the optionally substituted C₆₋₁₈ aryl-sulfonyl, C₆₋₁₀ aryl-sulfonylis preferable.

As the “heterocycle” moiety for the optionally substitutedheterocyclyl-carbonyl, 5- or 6-membered monocyclic heterocyclic groupcontaining, as ring-constituting atom, 1 to 3 hetero atoms selected fromoxygen atom, sulfur atom and nitrogen atom besides carbon atoms, and thelike are preferable, and pyridyl, furyl, tetrahydrofuryl, thienyl,pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, 1,2,3-triazolyl,1,2,3-thiadiazolyl, dihydrooxazolyl, pyridazinyl, pyrazinyl,dihydropyrazolyl, pyrrolyl, pyrrolidinyl, pyrimidinyl and the like arespecifically preferable. As the “substituent” for the optionallysubstituted heterocyclyl-carbonyl, (1) halogen atom (e.g., chlorine),(2) C₁₋₄ alkyl (e.g., methyl, ethyl, isopropyl, tert-butyl) optionallysubstituted by 1 to 3 substituents selected from halogen atom (e.g.,fluorine), cyano, hydroxy and C₁₋₄ alkoxy (e.g., methoxy) (specificexamples: methyl, trifluoromethyl, ethyl, methoxyethyl,2,2,2-trifluoroethyl, isopropyl, tert-butyl), (3) C₆₋₁₈ aryl (e.g.,phenyl), (4) C₆₋₁₀ aryl-C₁₋₄ alkyl (e.g., benzyl), (5) C₁₋₄ alkoxy(e.g., methoxy, ethoxy) optionally substituted by C₁₋₄ alkoxy (e.g.,methoxy) (specific examples: methoxy, ethoxy, methoxyethoxy), (6) C₁₋₄alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl), (7) C₁₋₄alkylcarbonyl (e.g., acetyl), (8) oxo, and the like are preferable.

As the optionally substituted heterocyclyl-carbonyl, 2-pyridylcarbonyl,3-pyridylcarbonyl, 4-pyridylcarbonyl, 2-methyl-6-pyridylcarbonyl,3-methyl-2-pyridylcarbonyl, 4-methyl-2-pyridylcarbonyl,2-methyl-3-pyridylcarbonyl, 2-(trifluoromethyl)-3-pyridylcarbonyl,2-(trifluoromethyl)-4-pyridylcarbonyl,2-(trifluoromethyl)-6-pyridylcarbonyl,2-chloro-6-methyl-4-pyridylcarbonyl, 2,6-dichloro-4-pyridylcarbonyl,2-furylcarbonyl, 2,5-dimethylfuran-3-carbonyl,5-methyl-2-(trifluoromethyl)-3-furancarbonyl,3-methylthiophene-2-carbonyl, 5-acetylsulfonylthiophene-2-carbonyl,5-ethylsulfonylthiophene-2-carbonyl,4-methyl-1,2,3-thiadiazole-5-carbonyl, isoxazole-5-carbonyl,1H-pyrazole-5-carbonyl, 1-methyl-1H-pyrazole-3-carbonyl,1-methyl-1H-pyrazole-5-carbonyl, 1-ethyl-1H-pyrazole-3-carbonyl,1-ethyl-1H-pyrazole-5-carbonyl, 3-methyl-1H-pyrazole-5-carbonyl,3-chloro-1-methyl-1H-pyrazole-5-carbonyl,4-chloro-1-methyl-1H-pyrazole-3-carbonyl,1-methyl-3-methoxy-1H-pyrazole-5-carbonyl,1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-carbonyl,3-methoxy-1-methyl-1H-pyrazole-4-carbonyl,3-methoxy-1-methyl-1H-pyrazole-5-carbonyl,3-ethoxy-1-methyl-1H-pyrazole-5-carbonyl,3-(2-methoxyethoxy)-1-methyl-1H-pyrazole-5-carbonyl,1-ethyl-3-methyl-1H-pyrazole-4-carbonyl,1-ethyl-3-methyl-1H-pyrazole-5-carbonyl,3-methyl-1-phenyl-1H-pyrazole-5-carbonyl,5-methyl-1-phenyl-1H-pyrazole-3-carbonyl,3-ethyl-1-methyl-1H-pyrazole-5-carbonyl,3-isopropyl-1-methyl-1H-pyrazole-5-carbonyl,3-methoxy-1-methyl-1H-pyrazole-5-carbonyl,1-tert-butyl-3-methyl-1H-pyrazole-5-carbonyl,3-tert-butyl-1-methyl-1H-pyrazole-5-carbonyl,1-methoxyethyl-3-methyl-1H-pyrazole-5-carbonyl,1,3-dimethyl-1H-pyrazole-4-carbonyl,1,3-dimethyl-1H-pyrazole-5-carbonyl,1,4-dimethyl-1H-pyrazole-3-carbonyl,1,4-dimethyl-1H-pyrazole-5-carbonyl,1,5-dimethyl-1H-pyrazole-3-carbonyl, 3-methylisoxazole-4-carbonyl,3-methylisoxazole-5-carbonyl, 5-methylisoxazole-3-carbonyl,5-methylisoxazole-4-carbonyl, 3,5-dimethylisoxazole-4-carbonyl,1,3-thiazole-2-carbonyl, 2-methyl-1,3-thiazole-4-carbonyl,4-methyl-1,3-thiazole-5-carbonyl, 5-methyl-1,3-thiazole-4-carbonyl,2,4-dimethyl-1,3-thiazole-5-carbonyl,2-chloro-4-methyl-1,3-thiazole-5-carbonyl,4-methoxy-2-methyl-1,3-thiazole-5-carbonyl,2-(1-hydroxy-1-methylethyl)-1,3-thiazole-5-carbonyl,2-(1-cyano-1-methylethyl)-1,3-thiazole-5-carbonyl,2-methyl-1,3-oxazole-4-carbonyl, 4-methyl-1,3-oxazole-5-carbonyl,2-ethyl-4-methyl-1,3-oxazole-5-carbonyl,2,4-dimethyl-1,3-oxazole-5-carbonyl,2,5-dimethyl-1,3-oxazole-4-carbonyl,1-methyl-1H-1,2,3-triazole-5-carbonyl,1-methyl-1H-1,2,3-triazole-4-carbonyl, 1-methyl-1H-imidazole-2-carbonyl,1-methyl-1H-imidazole-5-carbonyl, 2-pyrazinylcarbonyl,1-methylpyrrole-2-carbonyl, 1-benzylpyrrole-3-carbonyl,1,2,5-trimethylpyrrole-3-carbonyl, 1-methylpyrrolidine-2-carbonyl,2-(trifluoromethyl)pyrimidine-4-carbonyl and the like are specificallypreferable.

As the “heterocycle” moiety for the optionally substitutedheterocyclyl-sulfonyl, 5- or 6-membered monocyclic aromatic heterocyclicgroup containing, as ring-constituting atom, 1 to 3 heteroatoms selectedfrom oxygen atom, sulfur atom and nitrogen atom besides carbon atoms,and the like are preferable, and thiazolyl and the like are specificallypreferable. As the “substituent” for the optionally substitutedheterocyclyl-carbonyl, C₁₋₄ alkyl (e.g., methyl) and the like arepreferable.

As the optionally substituted heterocyclyl-sulfonyl,2,5-dimethyl-1,3-thiazole-4-sulfonyl and the like are specificallypreferable.

As the optionally substituted aminothiocarbonyl, aminothiocarbonyloptionally substituted by C₆₋₁₈ aryl-C₁₋₄ alkyl-carbonyl (e.g.,benzylcarbonyl) and the like are preferable.

(6) As the optionally esterified carboxy, carboxy and C₁₋₆alkoxy-carbonyl (e.g., methoxycarbonyl) are preferable.

Preferably, ring Y is

(1) C₆₋₁₀ aryl (e.g., phenyl) optionally substituted by 1 to 3substituents selected from

-   -   (a) halogen atom (e.g., fluorine, chlorine, bromine),    -   (b) C₁₋₄ alkyl (e.g., methyl, ethyl),    -   (c) C₁₋₄ alkoxy (e.g., methoxy),    -   (d) amino optionally substituted by substituents selected from        -   (i) C₁₋₄ alkyl (e.g., methyl) optionally substituted by            5-membered aromatic heterocyclic group (e.g., pyrazolyl)            optionally substituted by 1 to 3 C₁₋₄ alkyl (e.g., methyl),        -   (ii) C₁₋₄ alkyl-carbonyl (e.g., methylcarbonyl,            isobutylcarbonyl, tert-butylcarbonyl) optionally substituted            by 1 to 3 substituents selected from            -   (i′) hydroxy,            -   (ii′) C₁₋₄ alkylsulfonyl (e.g., methylsulfonyl), and            -   (iii′) 6-membered aromatic heterocyclic group (e.g.,                pyridyl),        -   (iii) C₂₋₄ alkenyl-carbonyl (e.g.,            2-methyl-1-propenylcarbonyl, vinylcarbonyl) optionally            substituted by C₆₋₁₀ aryl (e.g., phenyl),        -   (iv) C₂₋₄ alkynyl-carbonyl (e.g., acetylenecarbonyl,            1-propynylcarbonyl) optionally substituted by C₆₋₁₀ aryl            (e.g., phenyl),        -   (v) C₃₋₆ cycloalkyl-carbonyl (e.g., cyclopropylcarbonyl,            cyclopentylcarbonyl, cyclohexylcarbonyl),        -   (vi) C₃₋₆ cycloalkenyl-carbonyl (e.g.,            cyclopentenylcarbonyl),        -   (vii) C₆₋₁₀ aryl-carbonyl (e.g., benzoyl) optionally            substituted by 1 to 3 substituents selected from            -   (i′) halogen atom (e.g., fluorine, chlorine),            -   (ii′) C₁₋₄ alkyl (e.g., methyl, ethyl, isopropyl,                tert-butyl) optionally substituted by 1 to 3                substituents selected from halogen atom (e.g.,                fluorine), cyano, hydroxy and C₃₋₆ cycloalkyl (e.g.,                cyclopropyl),            -   (iii′) C₃₋₆ cycloalkyl (e.g., cyclopropyl, cyclobutyl,                cyclohexyl) optionally substituted by cyano,            -   (iv′) C₁₋₄ alkoxy (e.g., methoxy, ethoxy, isopropoxy,                tert-butoxy) optionally substituted by 1 to 5 halogen                atoms (e.g., fluorine),            -   (v′) C₁₋₄ alkoxy-carbonyl (e.g., methoxycarbonyl), and            -   (vi′) 5- or 6-membered heterocyclic group (e.g.,                tetrahydropyranyl, pyrrolidinyl) optionally substituted                by cyano or oxo,        -   (viii) 5- or 6-membered heterocyclyl-carbonyl containing, as            ring-constituting atom, 1 to 3 heteroatoms selected from            oxygen atom, sulfur atom and nitrogen atom besides carbon            atoms (e.g., furylcarbonyl, tetrahydrofurylcarbonyl,            thienylcarbonyl, pyrrolylcarbonyl, pyrrolidinylcarbonyl,            imidazolylcarbonyl, thiazolylcarbonyl, thiadiazolylcarbonyl,            dihydrooxazolylcarbonyl, oxazolylcarbonyl,            isoxazolylcarbonyl, pyrazolylcarbonyl,            dihydropyrazolylcarbonyl, triazolylcarbonyl,            pyridylcarbonyl, pyrimidinylcarbonyl, pyrazinylcarbonyl,            pyridazinylcarbonyl) optionally substituted by 1 to 3            substituents selected from            -   (i′) halogen atom (e.g., chlorine),            -   (ii′) C₁₋₄ alkyl (e.g., methyl, ethyl, isopropyl,                tert-butyl) optionally substituted by 1 to 3                substituents selected from halogen atom (e.g.,                fluorine), cyano, hydroxy and C₁₋₄ alkoxy (e.g.,                methoxy),            -   (iii′) C₆₋₁₀ aryl (e.g., phenyl),            -   (iv′) C₆₋₁₀ aryl-C₁₋₄ alkyl (e.g., benzyl),            -   (v′) C₁₋₄ alkoxy (e.g., methoxy, ethoxy) optionally                substituted by C₁₋₄ alkoxy (e.g., methoxy),            -   (vi′) C₁₋₄ alkylsulfonyl (e.g., methylsulfonyl,                ethylsulfonyl),            -   (vii′) C₁₋₄ alkyl-carbonyl (e.g., acetyl), and            -   (viii′) oxo,        -   (ix) aromatic fused heterocyclyl-carbonyl (e.g.,            benzopyrazolylcarbonyl, indolylcarbonyl),        -   (x) C₁₋₄ alkyl-aminocarbonyl (e.g., ethylaminocarbonyl),        -   (xi) C₆₋₁₀ aryl-aminocarbonyl (e.g., phenylaminocarbonyl)            optionally substituted by C₁₋₄ alkyl (e.g., methyl)            optionally substituted by 1 to 3 halogen atoms (e.g.,            fluorine),        -   (xii) C₁₋₄ alkoxy-aminocarbonyl (e.g., methoxyaminocarbonyl,            isobutoxyaminocarbonyl),        -   (xiii) 5-membered heterocyclyl-aminocarbonyl (e.g.,            isoxazolylaminocarbonyl, pyrazolylaminocarbonyl) optionally            substituted by 1 to 3 substituents selected from C₁₋₄ alkyl            (e.g., methyl, tert-butyl) and C₆₋₁₀ aryl (e.g., phenyl),        -   (xiv) aminothiocarbonyl optionally substituted by C₆₋₁₀            aryl-C₁₋₄ alkyl-carbonyl (e.g., benzylcarbonyl), and        -   (xv) 5-membered aromatic heterocyclyl-sulfonyl (e.g.,            thiazolylsulfonyl) optionally substituted by 1 to 3 C₁₋₄            alkyl (e.g., methyl),    -   (e) C₁₋₄ alkyl-aminocarbonyl (e.g., methylaminocarbonyl)        optionally having C₆₋₁₀ aryl (e.g., phenyl),    -   (f) 5-membered heterocyclyl-aminocarbonyl (e.g.,        pyrazolylaminocarbonyl) optionally substituted by 1 to 3        substituents selected from C₁₋₄ alkyl (e.g., methyl) and C₆₋₁₀        aryl,    -   (g) C₆₋₁₀ aryl-aminocarbonyl (e.g., phenylaminocarbonyl)        optionally substituted by C₁₋₄ alkyl (e.g., methyl, isopropyl,        tert-butyl) optionally substituted by 1 to 3 substituents        selected from halogen atom (e.g., fluorine) and cyano,    -   (h) carboxy, and    -   (i) nitro,        (2) monocyclic aromatic heterocycle (e.g., pyridyl) optionally        substituted by 1 to 3 substituents selected from    -   (a) halogen atom (e.g., bromine), and    -   (b) C₆₋₁₀ aryl-carbonylamino (e.g., benzoylamino) optionally        substituted by C₁₋₄ alkyl (e.g., methyl) optionally substituted        by 1 to 3 halogen atoms (e.g., fluorine), or        (3) fused aromatic heterocycle (e.g., indolyl, benzothiazolyl,        benzimidazolyl) optionally substituted by 1 to 3 substituents        selected from    -   (a) C₁₋₄ alkyl (e.g., methyl), and    -   (b) C₆₋₁₀ arylamino (e.g., phenylamino) optionally substituted        by C₁₋₄ alkyl (e.g., methyl) optionally substituted by 1 to 3        halogen atoms (e.g., fluorine),        and the like.

As ring Y, 3-[(1,3-dimethyl-1H-pyrazol-5-yl)aminocarbonyl]-3-phenyl,3-aminophenyl, 4-aminophenyl, 3-{[(ethylamino)carbonyl]amino}phenyl,4-{[(phenylamino)carbonyl]amino}phenyl,3-{[(phenylamino)carbonyl]amino}phenyl,3-({[3-(trifluoromethylphenyl)amino]carbonyl}amino)phenyl,3-({[4-(trifluoromethylphenyl)amino]carbonyl}amino)phenyl,3-[(tert-butylcarbonyl)amino]phenyl,3-[(cyclopropylcarbonyl)amino]phenyl,3-[(cyclohexylcarbonyl)amino]phenyl, 3-[(phenylcarbonyl)amino]phenyl,3-{[3-(trifluoromethylphenyl)carbonyl]amino}phenyl,3-{[3-(fluorophenyl)carbonyl]amino}phenyl,3-{[3-(chlorophenyl)carbonyl]amino}phenyl,3-{[3-(pyridyl)carbonyl]amino}phenyl,3-{[2-(furyl)carbonyl]amino}phenyl,3-{[3-(2,5-dimethylfuran)carbonyl]amino}phenyl,3-{[2-(3-methylthiophene)carbonyl]amino}phenyl,3-{[5-(4-methyl-1,2,3-thiadiazole)carbonyl]amino}phenyl,3-{[5-(isoxazole)carbonyl]amino}phenyl,3-{[5-(1,3-dimethyl-1H-pyrazole)carbonyl]amino}phenyl,3-{[5-(3-methylisoxazole)carbonyl]amino}phenyl,3-{[3-(5-methylisoxazole)carbonyl]amino}phenyl,3-({5-[1-methyl-3-(trifluoromethyl)-1H-pyrazole]carbonyl}amino)phenyl,5-methyl-2-(trifluoromethyl)-3-furancarbonylaminophenyl,3-{[5-(2,4-dimethyl-1,3-thiazole)carbonyl]amino}phenyl,3-{[4-(2,5-dimethyl-1,3-oxazole)carbonyl]amino}phenyl,3-{[5-(1-methyl-1H-pyrazole)carbonyl]amino}phenyl,3-{[3-(1,5-dimethyl-1H-pyrazole)carbonyl]amino}phenyl,3-{[4-(3,5-dimethylisoxazole)carbonyl]amino}phenyl,3-{[5-(1-methyl-1H-1,2,3-triazole)carbonyl]amino}phenyl,3-{[4-(1-methyl-1H-1,2,3-triazole)carbonyl]amino}phenyl,3-{[2-(1-methyl-1H-imidazole)carbonyl]amino}phenyl,3-{[5-(1-methyl-1H-imidazole)carbonyl]amino}phenyl, 1H-indol-6-yl,2-methyl-1H-indol-6-yl, 1,2-dimethyl-1H-benzimidazol-5-yl,1H-indol-4-yl, 2-methyl-1,3-benzothiazol-5-yl,2-methyl-1,3-benzothiazol-6-yl, 5-amino-2-methylphenyl,3-amino-2-methylphenyl, 3-amino-4-methylphenyl, 3-amino-4-chlorophenyl,5-amino-2-chlorophenyl, 5-amino-2-methoxyphenyl,6-methyl-3-{[5-(1,3-dimethyl-1H-pyrazole)carbonyl]amino}phenyl,2-methyl-3-{[5-(1,3-dimethyl-1H-pyrazole)carbonyl]amino}phenyl,4-methyl-3-{[5-(1,3-dimethyl-1H-pyrazole)carbonyl]amino}phenyl,4-chloro-3-{[5-(1,3-dimethyl-1H-pyrazole)carbonyl]amino}phenyl,6-chloro-3-{[5-(1,3-dimethyl-1H-pyrazole)carbonyl]amino}phenyl,4-fluoro-3-{[5-(1,3-dimethyl-1H-pyrazole)carbonyl]amino}phenyl,6-methoxy-3-{[5-(1,3-dimethyl-1H-pyrazole)carbonyl]amino}phenyl,4-chloro-3-(cyclopropylcarbonylamino)phenyl, 3-amino-4-fluorophenyl,4-fluoro-3-{[4-(1-ethyl-3-methyl-1H-pyrazole)carbonyl]amino}phenyl andthe like can be specifically mentioned.

In the compounds (I) and (IV), as the substituent for R of NR defined byX, those similar to the group exemplified as the “optionally substitutedhydrocarbon group” in the aforementioned Substituent Group (1)(iv), thegroup exemplified as the “optionally substituted aminocarbonyl” in theaforementioned Substituent Group (1)(viii), the group exemplified as the“acyl” in the aforementioned Substituent Group (1)(ix) and the groupexemplified as the “optionally substituted heterocyclic group” in theaforementioned Substituent Group (1)(xii) can be mentioned.

As the substituent for R, optionally substituted hydrocarbon group andthe like are preferable.

X is preferably —O—, —S— or —NH—, more preferably —O— or —S—, andparticularly preferably —O—.

In the compounds (I) and (IV), R¹ is hydrogen atom or substituent(provided that when R¹ is other than an optionally substituted amino,ring Y is a cyclic group substituted by an optionally substituted amino,wherein the cyclic group is optionally further substituted).

As the “substituent” for R¹, those similar to the substituent of theaforementioned Substituent Group (1) can be mentioned. Of these,optionally substituted amino, optionally substituted aminocarbonyl,optionally substituted alkyl and the like are preferable.

Preferable R¹ is

(1) hydrogen atom,

(2) amino,

(3) optionally substituted alkylcarbonylamino,

(4) optionally substituted alkenylcarbonylamino,

(5) optionally substituted alkynylcarbonylamino,

(6) optionally substituted cycloalkylcarbonylamino,

(7) optionally substituted cycloalkyl-alkylcarbonylamino,

(8) optionally substituted 6-membered heterocyclyl-carbonylamino,

(9) optionally substituted aminocarbonylamino,

(10) optionally substituted alkoxycarbonylamino,

(11) optionally substituted alkylsulfonylamino,

(12) optionally substituted cycloalkylsulfonylamino,

(13) optionally substituted arylamino,

(14) optionally substituted heterocyclylamino,

(15) optionally substituted aminocarbonyl,

(16) optionally substituted alkyl,

(17) optionally esterified carboxy, and the like.

Of these, preferable R¹ are

(1) hydrogen atom,

(2) amino,

(3) C₁₋₄ alkyl-carbonylamino (e.g., acetylamino, ethylcarbonylamino,isopropylcarbonylamino, isobutylcarbonylamino, tert-butylcarbonylamino)optionally substituted by 1 to 3 substituents selected from (a) halogenatom (e.g., chlorine), (b) hydroxy, (c) C₁₋₄ alkoxy (e.g., methoxy), (d)C₁₋₄ alkyl-carbonyloxy (e.g., methylcarbonyloxy), (e) C₁₋₄ alkylamino(e.g., methylamino), (f) di-C₁₋₄ alkylamino (e.g., dimethylamino), (g)C₁₋₄ alkylsulfonyl (e.g., methylsulfonyl), and (h) 6-memberedheterocyclic group (e.g., piperazinyl, morpholinyl) optionally having 1to 3 C₁₋₄ alkyl (e.g., methyl),(4) C₂₋₄ alkenyl-carbonylamino (e.g., vinylcarbonylamino,2-methyl-1-propenylcarbonylamino) optionally having C₁₋₄ alkoxy (e.g.,methoxy),(5) C₂₋₄ alkynyl-carbonylamino (e.g., 1-propenylcarbonylamino),(6) C₃₋₆ cycloalkyl-carbonylamino (e.g., cyclopropylcarbonylamino,cyclobutylcarbonylamino, cyclopentylcarbonylamino,cyclohexylcarbonylamino) optionally substituted by 1 to 4 substituentsselected from (a) halogen atom (e.g., fluorine), (b) hydroxy, (c) C₁₋₄alkyl (e.g., methyl, isopropyl) optionally having hydroxy, (d) C₁₋₄alkoxy (e.g., methoxy), (e) C₁₋₄ alkoxy-carbonyl (e.g.,methoxycarbonyl), and (f) C₁₋₄ alkyl-carbonyloxy (e.g., acetoxy),(7) C₃₋₆ cycloalkyl-C₁₋₄ alkyl-carbonylamino (e.g.,cyclopropylmethylcarbonylamino),(8) 6-membered heterocyclyl-carbonylamino (e.g.,tetrahydropyranylcarbonylamino, pyridylcarbonylamino,pyrimidinylcarbonylamino, morpholinylcarbonylamino,piperazinylcarbonylamino) optionally substituted by 1 to 3 substituentsselected from (a) halogen atom (e.g., fluorine, chlorine), (b) cyano,and (c) C₁₋₄ alkyl (e.g., methyl) optionally having 1 to 3 halogen atoms(e.g., fluorine),(9) aminocarbonylamino optionally substituted by 1 or 2 substituentsselected from (a) C₁₋₄ alkyl (e.g., ethyl) optionally having 1 to 3 C₁₋₄alkoxy (e.g., ethoxy) optionally having 1 to 3 hydroxy, and (b) C₁₋₄alkoxy (e.g., methoxy),(10) C₁₋₄ alkoxy-carbonylamino (e.g., methoxycarbonylamino,ethoxycarbonylamino, tert-butoxycarbonylamino) optionally substituted by1 to 3 halogen atoms (e.g., chlorine),(11) C₁₋₄ alkylsulfonylamino (e.g., methylsulfonylamino),(12) C₃₋₆ cycloalkylsulfonylamino (e.g., cyclopropylsulfonylamino),(13) C₆₋₁₀ arylamino (e.g., phenylamino),(14) heterocyclylamino (e.g., thiazolylamino, pyrimidinylamino)optionally substituted by 1 to 3 substituents selected from (a) halogenatom (e.g., chlorine), and (b) C₁₋₄ alkylamino (e.g., methylamino),(15) aminocarbonyl optionally substituted by C₁₋₄ alkyl (e.g., methyl),(16) C₁₋₄ alkyl (e.g., methyl) optionally substituted by hydroxy,(17) carboxy,(18) C₁₋₆ alkoxy-carbonyl (e.g., ethoxycarbonyl),and the like.

Specific R¹ may include hydrogen atom, amino, acetylamino,chloroacetylamino, 4-morpholinylacetylamino,methylcarbonyloxymethylcarbonylamino, methylaminomethylcarbonylamino,hydroxymethylcarbonylamino, methoxymethylcarbonylamino,ethylcarbonylamino, isopropylcarbonylamino,dimethylaminomethylcarbonylamino, 4-methylpiperazin-1-ylacetylamino,methylsulfonylmethylcarbonylamino, 3-hydroxy-3-methylbutanoylamino,hydroxyethylcarbonylamino, 3-methyl-2-butenoylamino,3-methoxy-2-propencylamino, 2-butynoylamino, (cyclopropylcarbonyl)amino,(1-methoxycarbonylcyclopropylcarbonyl)amino,(1-hydroxycyclopropylcarbonyl)amino, (2-methylcyclopropylcarbonyl)amino,(2-methoxycyclopropylcarbonyl)amino,(2-methylcarbonylcyclopropylcarbonyl)amino,(2-hydroxymethylcarbonylcyclopropylcarbonyl)amino,(2-(1-hydroxy-1-methylethyl)cyclopropyl)carbonylamino,(2,2-dimethylcyclopropylcarbonyl)amino,(2,2-difluorocyclopropylcarbonyl)amino,(2,2,3,3-tetramethylcyclopropylcarbonyl)amino,(cyclobutylcarbonyl)amino, (cyclopentylcarbonyl)amino,(cyclohexylcarbonyl)amino, cyclopropylmethylcarbonylamino,(tetrahydro-2H-pyran-4-ylcarbonyl)amino, (3-pyridylcarbonyl)amino,(4-pyridylcarbonyl)amino, (6-methyl-3-pyridylcarbonyl)amino,(6-fluoro-3-pyridylcarbonyl)amino, (6-chloro-3-pyridylcarbonyl)amino,(6-cyano-3-pyridylcarbonyl)amino,(6-(trifluoromethyl)-3-pyridylcarbonyl)amino,(5-pyrimidinylcarbonyl)amino, 4-morpholinylcarbonylamino, methoxyureido,ethylureido, 2-hydroxyethoxyethylureido, methoxycarbonylamino,ethoxycarbonylamino, 2,2,2-trichloroethoxycarbonylamino,tert-butoxycarbonylamino, methylsulfonylamino,(cyclopropylsulfonyl)amino, phenylamino,2-methylaminopyrimidin-4-ylamino, 2-chloropyrimidin-4-ylamino,1,3-thiazol-2-ylamino, methylaminocarbonyl, hydroxymethyl, carboxy,ethoxycarbonyl and the like can be mentioned.

In the compounds (I) and (IV), as the “substituent” for R², thosesimilar to the substituents of the aforementioned Substituent Group (1)can be mentioned.

Of these, preferable R² is hydrogen atom.

In the compounds (I) and (IV), as the “substituent” for R³, thosesimilar to the substituents of the aforementioned Substituent Group (1)can be mentioned.

Of these, preferable R³ is hydrogen atom.

In the compounds (I) and (IV), as the “substituent” for R⁴, thosesimilar to the substituents of the aforementioned Substituent Group (1)can be mentioned.

Of these, preferable R⁴ is hydrogen atom.

As preferable examples of the compounds (I) and (IV), for example, thefollowing compounds can be mentioned.

A compound wherein

ring Y is

(1) C₆₋₁₀ aryl optionally substituted by 1 to 3 substituents selectedfrom

-   -   (a) halogen atom,    -   (b) C₁₋₄ alkyl,    -   (c) C₁₋₄ alkoxy,    -   (d) amino optionally substituted by the substituents selected        from        -   (i) C₁₋₄ alkyl optionally substituted by a 5-membered            aromatic heterocyclic group optionally substituted by 1 to 3            C₁₋₄ alkyl,        -   (ii) C₁₋₄ alkyl-carbonyl optionally substituted by 1 to 3            substituents selected from            -   (i′) hydroxy,            -   (ii′) C₁₋₄ alkylsulfonyl, and            -   (iii′) 6-membered aromatic heterocyclic group,        -   (iii) C₂₋₄ alkenyl-carbonyl optionally substituted by C₆₋₁₀            aryl,        -   (iv) C₂₋₆ alkynyl-carbonyl optionally substituted by C₆₋₁₀            aryl,        -   (v) C₃₋₆ cycloalkyl-carbonyl,        -   (vi) C₃₋₆ cycloalkenyl-carbonyl,        -   (vii) C₆₋₁₀ aryl-carbonyl optionally substituted by 1 to 3            substituents selected from            -   (i′) halogen atom,            -   (ii′) C₁₋₄ alkyl optionally substituted by 1 to 3                substituents selected from halogen atom, cyano, hydroxy                and C₃₋₆ cycloalkyl,            -   (iii′) C₃₋₆ cycloalkyl optionally substituted by cyano,            -   (iv′) C₁₋₄ alkoxy optionally substituted by 1 to 5                halogen atoms,            -   (v′) C₁₋₄ alkoxy-carbonyl, and            -   (vi′) 5- or 6-membered heterocyclic group optionally                substituted by cyano or oxo,        -   (viii) 5- or 6-membered heterocyclyl-carbonyl containing, as            ring-constituting atom, 1 to 3 heteroatoms selected from            oxygen atom, sulfur atom and nitrogen atom besides carbon            atoms, which is optionally substituted by 1 to 3            substituents selected from            -   (i′) halogen atom,            -   (ii′) C₁₋₄ alkyl optionally substituted by 1 to 3                substituents selected from halogen atom, cyano, hydroxy                and C₁₋₄ alkoxy,            -   (iii′) C₆₋₁₀ aryl,            -   (iv′) C₆₋₁₀ aryl-C₁₋₄ alkyl,            -   (v′) C₁₋₄ alkoxy optionally substituted by C₁₋₄ alkoxy,            -   (vi′) C₁₋₄ alkylsulfonyl,            -   (vii′) C₁₋₄ alkyl-carbonyl, and            -   (viii′) oxo,        -   (ix) aromatic fused heterocyclyl-carbonyl,        -   (x) C₁₋₄ alkyl-aminocarbonyl,        -   (xi) C₆₋₁₀ aryl-aminocarbonyl optionally substituted by C₁₋₄            alkyl optionally substituted by 1 to 3 halogen atoms,        -   (xii) C₁₋₄ alkoxy-aminocarbonyl,        -   (xiii) 5-membered heterocyclyl-aminocarbonyl optionally            substituted by 1 to 3 substituents selected from C₁₋₄ alkyl            and C₆₋₁₀ aryl,        -   (xiv) aminothiocarbonyl optionally substituted by C₆₋₁₀            aryl-C₁₋₄ alkyl-carbonyl, and        -   (xv) 5-membered aromatic heterocyclyl-sulfonyl optionally            substituted by 1 to 3 C₁₋₄ alkyl,    -   (e) C₁₋₄ alkyl-aminocarbonyl optionally having C₆₋₁₀ aryl,    -   (f) 5-membered heterocyclyl-aminocarbonyl optionally substituted        by 1 to 3 substituents selected from C₁₋₄ alkyl and C₆₋₁₀ aryl,    -   (g) C₆₋₁₀ aryl-aminocarbonyl optionally substituted by C₁₋₄        alkyl optionally substituted by 1 to 3 substituents selected        from halogen atom and cyano,    -   (h) carboxy, and    -   (i) nitro,        (2) monocyclic aromatic heterocycle optionally substituted by 1        to 3 substituents selected from    -   (a) halogen atom, and    -   (b) C₆₋₁₀ aryl-carbonylamino optionally substituted by C₁₋₄        alkyl optionally substituted by 1 to 3 halogen atoms, or        (3) fused aromatic heterocycle optionally substituted by 1 to 3        substituents selected from    -   (a) C₁₋₄ alkyl, and    -   (b) C₆₋₁₀ arylamino optionally substituted by C₁₋₄ alkyl        optionally substituted by 1 to 3 halogen atoms;        X is —O—, —S— or —NH— (more preferably —O— or —S—, particularly        preferably —O—);        R¹ is    -   (1) hydrogen atom,    -   (2) amino,    -   (3) C₁₋₄ alkyl-carbonylamino optionally substituted by 1 to 3        substituents selected from        -   (a) halogen atom,        -   (b) hydroxy,        -   (c) C₁₋₄ alkoxy,        -   (d) C₁₋₄ alkyl-carbonyloxy,        -   (e) C₁₋₄ alkylamino,        -   (f) di-C₁₋₄ alkylamino,        -   (g) C₁₋₄ alkylsulfonyl, and        -   (h) 6-membered heterocyclic group optionally having 1 to 3            C₁₋₄ alkyl,            (4) C₂₋₄ alkenyl-carbonylamino optionally having C₁₋₄            alkoxy,            (5) C₂₋₄ alkynyl-carbonylamino,            (6) C₃₋₆ cycloalkyl-carbonylamino optionally substituted by            1 to 4 substituents selected from    -   (a) halogen atom,    -   (b) hydroxy,    -   (c) C₁₋₄ alkyl optionally having hydroxy,    -   (d) C₁₋₄ alkoxy,    -   (e) C₁₋₄ alkoxy-carbonyl, and    -   (f) C₁₋₄ alkyl-carbonyloxy,        (7) C₃₋₆ cycloalkyl-C₁₋₄ alkyl-carbonylamino,        (8) 6-membered heterocyclyl-carbonylamino optionally substituted        by 1 to 3 substituents selected from    -   (a) halogen atom,    -   (b) cyano, and    -   (c) C₁₋₄ alkyl optionally having 1 to 3 halogen atom,        (9) aminocarbonylamino optionally substituted by 1 or 2        substituents selected from    -   (a) C₁₋₄ alkyl optionally having 1 to 3 C₁₋₄ alkoxy optionally        having 1 to 3 hydroxy, and    -   (b) C₁₋₄ alkoxy,        (10) C₁₋₄ alkoxy-carbonylamino optionally substituted by 1 to 3°        halogen atoms,        (11) C₁₋₄ alkylsulfonylamino,        (12) C₃₋₆ cycloalkylsulfonylamino,        (13) C₆₋₁₀ arylamino,        (14) heterocyclylamino optionally substituted by 1 to 3        substituents selected from    -   (a) halogen atom, and    -   (b) C₁₋₄ alkylamino,        (15) aminocarbonyl substituted by C₁₋₄ alkyl (e.g., methyl        etc.),        (16) C₁₋₄ alkyl (e.g., methyl) optionally substituted by        hydroxy,        (17) carboxy, or        (18) C₁₋₆ alkoxy-carbonyl (e.g., ethoxycarbonyl); and        R², R³ and R⁴ are each hydrogen atom.

As specific examples of the compounds (I) and (IV), for example,compounds of Examples 1 to 440, 442 and 445 can be mentioned.

Particularly preferable examples may include the following compounds orsalts thereof.

-   N-{3-[(2-{[2-(methylamino)pyrimidin-4-yl]amino}imidazol[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide    (Example 70);-   N-[2-chloro-5-({2-[(cyclopropylcarbonyl)amino]imidazol[1,2-b]pyridazin-6-yl}oxy)phenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide    (Example 97);-   N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide    (Example 111);-   N-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-2,4-dimethyl-1,3-thiazole-5-carboxamide    (Example 114);-   N-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-2,5-dimethyl-1,3-oxazole-4-carboxamide    (Example 117);-   N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide    (Example 148);-   N-[3-({2-[(N,N-dimethylglycyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide    (Example 149);-   N-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}sulfanyl)phenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide    (Example 150);-   N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-1-ethyl-3-methyl-1H-pyrazole-4-carboxamide    (Example 161);-   N-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]benzamide    (Example 165);-   N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-1,3-dimethyl-1H-pyrazole-4-carboxamide    (Example 173);-   N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-1-ethyl-1H-pyrazole-5-carboxamide    (Example 174);-   N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-3-methoxy-1-methyl-1H-pyrazole-5-carboxamide    (Example 180);-   N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-3-ethyl-1-methyl-1H-pyrazole-5-carboxamide    (Example 208);-   N-[2-chloro-5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-1-ethyl-3-methyl-1H-pyrazole-4-carboxamide    (Example 254);-   N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-1-methyl-1H-pyrazole-5-carboxamide    (Example 287);-   N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-2,4-dimethyl-1,3-oxazole-5-carboxamide    (Example 289);-   N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-2-ethyl-4-methyl-1,3-oxazole-5-carboxamide    (Example 314);-   N-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-3-(trifluoromethyl)benzamide    (Example 319);-   3-(1-cyano-1-methylethyl)-N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]benzamide    (Example 330);-   N-[3-({2-[(N,N-dimethylglycyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-3-(trifluoromethyl)benzamide    (Example 398);-   N-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}thio)phenyl]-3-(trifluoromethyl)benzamide    (Example 427);-   N-{6-[3-({[3-(trifluoromethyl)phenyl]carbamoyl}amino)phenoxy]imidazo[1,2-b]pyridazin-2-yl}cyclopropanecarboxamide    (Example 431).

The compound represented by the formula (II) (hereinafter compound (II))of the present invention is explained.

As the “cyclic group” of the “optionally substituted cyclic group” forring Ya, those similar to the group exemplified as the “cyclic group” ofthe “optionally substituted cyclic group” for ring Y of compound (I) canbe mentioned.

As the “cyclic group” of the “optionally substituted cyclic group” shownby ring Ya, aromatic hydrocarbon group, aromatic heterocyclic group arepreferable. As the aromatic hydrocarbon group, C₆₋₁₄ aryl is preferable,C₆₋₁₀ aryl is more preferable, and phenyl is particularly preferable. Asthe aromatic heterocyclic group, monocyclic aromatic heterocyclic group,fused aromatic heterocyclic group are preferable, pyridine ring, and,fused aromatic heterocyclic group formed by fusion of benzene ring and5-membered monocyclic aromatic heterocyclic group containing, asring-constituting atom, 1 or 2 hetero atoms selected from sulfur atomand nitrogen atom besides carbon atoms (e.g., benzothiazolyl,benzimidazolyl, indolyl etc.) is more preferable, and benzothiazolyl(e.g., 5-benzothiazolyl, 6-benzothiazolyl), benzimidazolyl (e.g.,benzimidazol-5-yl, benzimidazol-6-yl), indolyl (e.g., indol-4-yl,indol-5-yl, indol-6-yl) and the like are particularly preferable.

The “optionally substituted cyclic group” for ring Ya may have 1 to theacceptable maximum number of substituents at any substitutablepositions. Where the cyclic group is substituted by two or moresubstituents, the substituents may be the same or different, and thecyclic group optionally has preferably 1 to 5, more preferably 1 to 3substituents.

As the “substituent” of the “optionally substituted cyclic group” forring Ya, those similar to the group exemplified as the “substituent” ofthe “optionally substituted cyclic group” for ring Y of compound (I) canbe mentioned.

The “substituent” of the “optionally substituted cyclic group” for ringYa is preferably

(1) halogen atom (e.g., fluorine, chlorine, bromine, iodine),

(2) optionally substituted alkyl,

(3) optionally substituted alkoxy,

(4) optionally substituted aminocarbonyl,

(5) optionally substituted amino,

(6) carboxyl,

and the like.

Of these,

(1) halogen atom (e.g., fluorine, chlorine, bromine, iodine),

(2) optionally substituted alkyl,

(3) optionally substituted amino,

and the like are preferable.

Hereinafter the above-mentioned preferable examples of the “substituent”of the “optionally substituted cyclic group” for ring Ya are explainedin detail.

(1) As the halogen atom, fluorine, chlorine, bromine and the like arepreferable.

(2) As the optionally substituted alkyl, optionally substituted C₁₋₈alkyl is preferable, optionally substituted C₁₋₄ alkyl is morepreferable, and unsubstituted C₁₋₄ alkyl is more preferable.Specifically, methyl, ethyl and the like are preferable.

(3) As the optionally substituted alkoxy, optionally substituted C₁₋₈alkoxy is preferable, optionally substituted C₁₋₄ alkoxy is morepreferable, unsubstituted C₁₋₄ alkoxy is much more preferable.Specifically, methoxy and the like are preferable.

(4) As the “substituent” for the optionally substituted aminocarbonyl,for example, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₈ cycloalkyl,C₃₋₈ cycloalkenyl, C₃₋₈ cycloalkynyl, C₆₋₁₈ aryl, heterocyclic group andthe like, each of which is optionally substituted, are preferable. Ofthese, optionally substituted C₁₋₄ alkyl, optionally substituted C₆₋₁₂aryl and optionally substituted 5-membered heterocyclic group and thelike are preferable. Particularly, C₆₋₁₂ aryl optionally substituted byC₁₋₄ alkyl optionally substituted by 1 to 3 substituents selected from(a) C₁₋₄ alkyl optionally having C₆₋₁₂ aryl, (b) 5-membered heterocyclicgroup optionally substituted by 1 to 3 substituents selected from C₁₋₄alkyl and C₆₋₁₂ aryl, (c) halogen atom and (d) cyano is preferable.(5) As the “substituent” for the optionally substituted amino,optionally substituted alkyl, optionally substituted aminocarbonyl,acyl, optionally substituted aminothiocarbonyl, optionally substitutedheterocyclyl-sulfonyl and the like are preferable.

As the optionally substituted amino, amino optionally substituted by 1or 2 substituents selected from (a) optionally substituted alkyl, (b)optionally substituted aminocarbonyl, (c) acyl, (d) optionallysubstituted aminothiocarbonyl, and (e) optionally substitutedheterocyclyl-sulfonyl is preferable.

As the optionally substituted alkyl, optionally substituted C₁₋₄ alkylis preferable. Of these, C₁₋₄ alkyl optionally substituted by 5-memberedheterocyclic group optionally substituted by 1 to 3 C₁₋₄ alkyl ispreferable.

As the optionally substituted aminocarbonyl, C₁₋₈ alkyl-aminocarbonyl,C₆₋₁₈ aryl-aminocarbonyl, C₆₋₁₈ aryl-C₁₋₄-alkyl-aminocarbonyl,heterocyclyl-aminocarbonyl, C₃₋₈ cycloalkyl-aminocarbonyl, C₁₋₈alkoxy-aminocarbonyl and the like, each of which is optionallysubstituted, are preferable. Of these, optionally substituted C₁₋₈alkyl-aminocarbonyl, optionally substituted C₆₋₁₈ aryl-aminocarbonyl,optionally substituted heterocyclyl-aminocarbonyl, optionallysubstituted C₁₋₈ alkoxy-aminocarbonyl and the like are preferable.Particularly, (i) C₁₋₄ alkyl-aminocarbonyl, (ii) C₆₋₁₀aryl-aminocarbonyl optionally substituted by C₁₋₄ alkyl optionallysubstituted by 1 to 3 halogen atoms, (iii) C₁₋₄ alkoxy-aminocarbonyl,(iv) 5-membered heterocyclyl-aminocarbonyl optionally substituted by 1to 3 substituents selected from C₁₋₄ alkyl and C₆₋₁₀ aryl, and the likeare preferable.

As the acyl, C₁₋₈ alkyl-carbonyl, C₂₋₈ alkenyl-carbonyl, C₂₋₈alkynyl-carbonyl, C₃₋₈ cycloalkyl-carbonyl, C₃₋₈ cycloalkenyl-carbonyl,C₆₋₁₈ aryl-carbonyl, C₆₋₁₈ aryl-C₁₋₄ alkyl-carbonyl, C₁₋₈ alkylsulfonyl,C₆₋₁₈ aryl-sulfonyl, heterocyclyl-carbonyl, heterocyclyl-sulfonyl andthe like, each of which is optionally substituted, are preferable. Ofthese, C₁₋₈ alkyl-carbonyl, C₂₋₈ alkenyl-carbonyl, C₂₋₈alkynyl-carbonyl, C₃₋₈ cycloalkyl-carbonyl, C₃₋₈ cycloalkenyl-carbonyl,C₆₋₁₈ aryl-carbonyl, heterocyclyl-carbonyl, each of which is optionallysubstituted, are preferable.

As the optionally substituted C₁₋₈ alkyl-carbonyl, optionallysubstituted C₁₋₄ alkyl-carbonyl is preferable. Particularly, C₁₋₄alkyl-carbonyl (e.g., methylcarbonyl, tert-butylcarbonyl,3-methylbutanoyl) optionally substituted by 1 to 3 substituents selectedfrom (a) hydroxy, (b) C₁₋₄ alkylsulfonyl (e.g., methylsulfonyl) and (c)6-membered heterocyclic group (e.g., pyridyl) (specific examples:methylsulfonylmethylcarbonyl, 2-pyridylmethylcarbonyl,tert-butylcarbonyl, 3-hydroxy-3-methylbutanoyl) is preferable.

As the optionally substituted C₂₋₈ alkenyl-carbonyl, optionallysubstituted C₂₋₄ alkenyl-carbonyl is preferable. Particularly, C₂₋₄alkenyl-carbonyl (e.g., 3-methyl-2-butenoyl) optionally substituted byC₆₋₁₀ aryl (e.g., phenyl) (specific examples: 3-methyl-2-butenoyl) ispreferable.

As the optionally substituted C₂₋₈ alkynyl-carbonyl, optionallysubstituted C₂₋₄ alkynyl-carbonyl is preferable. Particularly, C₂₋₄alkynyl-carbonyl (e.g., 2-butynoyl) optionally substituted by C₆₋₁₀ aryl(e.g., phenyl) (specific example: 2-butynoyl) is preferable.

As the optionally substituted C₃₋₈ cycloalkyl-carbonyl, C₃₋₆cycloalkyl-carbonyl is preferable, and cyclopropylcarbonyl,cyclopentylcarbonyl, cyclohexylcarbonyl and the like are specificallypreferable.

As the optionally substituted C₃₋₈ cycloalkenyl-carbonyl, C₃₋₆cycloalkenyl-carbonyl (e.g., cyclopentenecarbonyl) (specific example:1-cyclopentenecarbonyl) is preferable.

As the optionally substituted C₆₋₁₈ aryl-carbonyl, optionallysubstituted C₆₋₁₀ aryl-carbonyl is preferable. Particularly, C₆₋₁₀aryl-carbonyl (e.g., benzoyl) optionally substituted by 1 to 3substituents selected from (a) halogen atom (e.g., fluorine), (b) C₁₋₄alkyl (e.g., methyl, ethyl, isopropyl, tert-butyl) optionallysubstituted by 1 to 3 substituents selected from halogen atom (e.g.,fluorine), cyano, hydroxy and C₃₋₆ cycloalkyl (e.g., cyclopropyl)(specific example: trifluoromethyl), (c) C₃₋₆ cycloalkyl (e.g.,cyclopropyl, cyclobutyl, cyclohexyl) optionally substituted by cyano,(d) C₁₋₄ alkoxy (e.g., isopropoxy, tert-butoxy) optionally substitutedby 1 to 5 halogen atoms (e.g., fluorine), (e) C₁₋₄ alkoxy-carbonyl(e.g., methoxycarbonyl), and (f) 5 or 6-membered heterocyclic group(e.g., tetrahydropyranyl, pyrrolidinyl) optionally substituted by cyanoor oxo is preferable. Specifically, phenylcarbonyl(benzoyl),3-(trifluoromethyl)phenylcarbonyl, 4-(trifluoromethyl)phenylcarbonyl,3-fluorophenylcarbonyl, 3-chlorophenylcarbonyl,3-(1-cyanocyclopropyl)phenylcarbonyl,3-(1-cyanocyclobutyl)phenylcarbonyl,3-(1-cyanocyclohexyl)phenylcarbonyl,2-fluoro-3-(trifluoromethyl)phenylcarbonyl,2-fluoro-5-(trifluoromethyl)phenylcarbonyl,3-fluoro-5-(trifluoromethyl)phenylcarbonyl,4-chloro-3-(trifluoromethyl)phenylcarbonyl,2-chloro-3-(trifluoromethyl)phenylcarbonyl,2-chloro-5-(trifluoromethyl)phenylcarbonyl, 3-isopropoxyphenylcarbonyl,3-(tert-butoxy)phenylcarbonyl, 3-(1-cyano-1-methylethyl)phenylcarbonyl,3-methoxyphenylcarbonyl, 3-methoxycarbonylphenylcarbonyl,3-(trifluoromethoxy)carbonylphenylcarbonyl,3-(1,1,2,2-tetrafluoroethoxy)phenylcarbonyl,3-(4-cyanotetrahydropyran-4-yl)phenylcarbonyl,3,5-di(trifluoromethyl)phenylcarbonyl,3-(2-oxopyrrolidin-1-yl)phenylcarbonyl, 4-(tert-butyl)phenylcarbonyl,3-(1-cyanoethyl)phenylcarbonyl,3-(1-cyano-2-cyclopropyl-1-methylethyl)phenylcarbonyl and the like arepreferable.

As the optionally substituted C₆₋₁₈ aryl-C₁₋₄ alkyl-carbonyl, C₆₋₁₀aryl-C₁₋₄ alkyl-carbonyl is preferable.

As the optionally substituted C₁₋₈ alkylsulfonyl, C₁₋₄ alkylsulfonyl arepreferable.

As the optionally substituted C₆₋₁₈ aryl-sulfonyl, C₆₋₁₀ aryl-sulfonylis preferable.

As the “heterocycle” moiety for the optionally substitutedheterocyclyl-carbonyl, 5- or 6-membered monocyclic heterocyclic groupcontaining, as ring-constituting atom, 1 to 3 hetero atoms selected fromoxygen atom, sulfur atom and nitrogen atom besides carbon atoms, and thelike are preferable, and pyridyl, furyl, tetrahydrofuryl, thienyl,pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, 1,2,3-triazolyl,1,2,3-thiadiazolyl, dihydrooxazolyl, pyridazinyl, pyrazinyl,dihydropyrazolyl, pyrrolyl, pyrrolidinyl, pyrimidinyl and the like arespecifically preferable. As the “substituent” for the optionallysubstituted heterocyclyl-carbonyl, (1) halogen atom (e.g., chlorine),(2) C₁₋₄ alkyl (e.g., methyl, ethyl, isopropyl, tert-butyl) optionallysubstituted by 1 to 3 substituents selected from halogen atom (e.g.,fluorine), cyano, hydroxy and C₁₋₄ alkoxy (e.g., methoxy) (specificexamples: methyl, trifluoromethyl, ethyl, methoxyethyl,2,2,2-trifluoroethyl, isopropyl, tert-butyl), (3) C₆₋₁₈ aryl (e.g.,phenyl), (4) C₆₋₁₀ aryl-C₁₋₄ alkyl (e.g., benzyl), (5) C₁₋₄ alkoxy(e.g., methoxy, ethoxy) optionally substituted by C₁₋₄ alkoxy (e.g.,methoxy) (specific examples: methoxy, ethoxy, methoxyethoxy), (6) C₁₋₄alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl), (7) C₁₋₄alkylcarbonyl (e.g., acetyl), (8) oxo, and the like are preferable.

As the optionally substituted heterocyclyl-carbonyl, the above-mentioned5- or 6-membered monocyclic aromatic heterocyclyl-carbonyl and the likeoptionally substituted by optionally halogenated C₁₋₄ alkyl and the likeare preferable. Specifically, 2-pyridylcarbonyl, 3-pyridylcarbonyl,4-pyridylcarbonyl, 2-methyl-6-pyridylcarbonyl,3-methyl-2-pyridylcarbonyl, 4-methyl-2-pyridylcarbonyl,2-methyl-3-pyridylcarbonyl, 2-(trifluoromethyl)-3-pyridylcarbonyl,2-(trifluoromethyl)-4-pyridylcarbonyl,2-(trifluoromethyl)-6-pyridylcarbonyl,2-chloro-6-methyl-4-pyridylcarbonyl, 2,6-dichloro-4-pyridylcarbonyl,2-furylcarbonyl, 2,5-dimethylfuran-3-carbonyl,5-methyl-2-(trifluoromethyl)-3-furancarbonyl,3-methylthiophene-2-carbonyl, 5-acetylsulfonylthiophene-2-carbonyl,5-ethylsulfonylthiophene-2-carbonyl,4-methyl-1,2,3-thiadiazole-5-carbonyl, isoxazole-5-carbonyl,1H-pyrazole-5-carbonyl, 1-methyl-1H-pyrazole-3-carbonyl,1-methyl-1H-pyrazole-5-carbonyl, 1-ethyl-1H-pyrazole-3-carbonyl,1-ethyl-1H-pyrazole-5-carbonyl, 3-methyl-1H-pyrazole-5-carbonyl,3-chloro-1-methyl-1H-pyrazole-5-carbonyl,4-chloro-1-methyl-1H-pyrazole-3-carbonyl,1-methyl-3-methoxy-1H-pyrazole-5-carbonyl,1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-carbonyl,3-methoxy-1-methyl-1H-pyrazole-4-carbonyl,3-methoxy-1-methyl-1H-pyrazole-5-carbonyl,3-ethoxy-1-methyl-1H-pyrazole-5-carbonyl,3-(2-methoxyethoxy)-1-methyl-1H-pyrazole-5-carbonyl,1-ethyl-3-methyl-1H-pyrazole-4-carbonyl,1-ethyl-3-methyl-1H-pyrazole-5-carbonyl,3-methyl-1-phenyl-1H-pyrazole-5-carbonyl,5-methyl-1-phenyl-1H-pyrazole-3-carbonyl,3-ethyl-1-methyl-1H-pyrazole-5-carbonyl,3-isopropyl-1-methyl-1H-pyrazole-5-carbonyl,3-methoxy-1-methyl-1H-pyrazole-5-carbonyl,1-tert-butyl-3-methyl-1H-pyrazole-5-carbonyl,3-tert-butyl-1-methyl-1H-pyrazole-5-carbonyl,1-methoxyethyl-3-methyl-1H-pyrazole-5-carbonyl,1,3-dimethyl-1H-pyrazole-4-carbonyl,1,3-dimethyl-1H-pyrazole-5-carbonyl,1,4-dimethyl-1H-pyrazole-3-carbonyl,1,4-dimethyl-1H-pyrazole-5-carbonyl,1,5-dimethyl-1H-pyrazole-3-carbonyl, 3-methylisoxazole-4-carbonyl,3-methylisoxazole-5-carbonyl, 5-methylisoxazole-3-carbonyl,5-methylisoxazole-4-carbonyl, 3,5-dimethylisoxazole-4-carbonyl,1,3-thiazole-2-carbonyl, 2-methyl-1,3-thiazole-4-carbonyl,4-methyl-1,3-thiazole-5-carbonyl, 5-methyl-1,3-thiazole-4-carbonyl,2,4-dimethyl-1,3-thiazole-5-carbonyl,2-chloro-4-methyl-1,3-thiazole-5-carbonyl,4-methoxy-2-methyl-1,3-thiazole-5-carbonyl,2-(1-hydroxy-1-methylethyl)-1,3-thiazole-5-carbonyl,2-(1-cyano-1-methylethyl)-1,3-thiazole-5-carbonyl,2-methyl-1,3-oxazole-4-carbonyl, 4-methyl-1,3-oxazole-5-carbonyl,2-ethyl-4-methyl-1,3-oxazole-5-carbonyl,2,4-dimethyl-1,3-oxazole-5-carbonyl,2,5-dimethyl-1,3-oxazole-4-carbonyl,1-methyl-1H-1,2,3-triazole-5-carbonyl,1-methyl-1H-1,2,3-triazole-4-carbonyl, 1-methyl-1H-imidazole-2-carbonyl,1-methyl-1H-imidazole-5-carbonyl, 2-pyrazinylcarbonyl,1-methylpyrrole-2-carbonyl, 1-benzylpyrrole-3-carbonyl,1,2,5-trimethylpyrrole-3-carbonyl, 1-methylpyrrolidine-2-carbonyl,2-(trifluoromethyl)pyrimidine-4-carbonyl and the like are preferable.

As the “heterocycle” moiety for the optionally substitutedheterocyclyl-sulfonyl, 5- or 6-membered monocyclic aromatic heterocyclicgroup containing, as ring-constituting atom, 1 to 3 heteroatoms selectedfrom oxygen atom, sulfur atom and nitrogen atom besides carbon atoms,and the like are preferable, and thiazolyl and the like are specificallypreferable. As the “substituent” for the optionally substitutedheterocyclyl-carbonyl, C₁₋₄ alkyl (e.g., methyl) and the like arepreferable.

As the optionally substituted heterocyclyl-sulfonyl,2,5-dimethyl-1,3-thiazole-4-sulfonyl and the like are specificallypreferable.

As the optionally substituted aminothiocarbonyl, aminothiocarbonyloptionally substituted by C₆₋₁₈ aryl-C₁₋₄ alkyl-carbonyl (e.g.,benzylcarbonyl) and the like are preferable.

Preferably, ring Ya is

(1) C₆₋₁₀ aryl (e.g., phenyl) optionally substituted by 1 to 3substituents selected from

-   -   (a) halogen atom (e.g., fluorine, chlorine, bromine),    -   (b) C₁₋₄ alkyl (e.g., methyl, ethyl),    -   (c) C₁₋₄ alkoxy (e.g., methoxy),    -   (d) amino optionally substituted by substituents selected from        -   (i) C₁₋₄ alkyl (e.g., methyl) optionally substituted by            5-membered aromatic heterocyclic group (e.g., pyrazolyl)            optionally substituted by 1 to 3 C₁₋₄ alkyl (e.g., methyl),        -   (ii) C₁₋₄ alkyl-carbonyl (e.g., methylcarbonyl,            isobutylcarbonyl, tert-butylcarbonyl) optionally substituted            by 1 to 3 substituents selected from            -   (i′) hydroxy,            -   (ii′) C₁₋₄ alkylsulfonyl (e.g., methylsulfonyl), and            -   (iii′) 6-membered aromatic heterocyclic group (e.g.,                pyridyl),        -   (iii) C₂₋₄ alkenyl-carbonyl (e.g.,            2-methyl-1-propenylcarbonyl, vinylcarbonyl) optionally            substituted by C₆₋₁₀ aryl (e.g., phenyl),        -   (iv) C₂₋₄ alkynyl-carbonyl (e.g., acetylenecarbonyl,            1-propynylcarbonyl) optionally substituted by C₆₋₁₀ aryl            (e.g., phenyl),        -   (v) C₃₋₆ cycloalkyl-carbonyl (e.g., cyclopropylcarbonyl,            cyclopentylcarbonyl, cyclohexylcarbonyl),        -   (vi) C₃₋₆ cycloalkenyl-carbonyl (e.g.,            cyclopentenylcarbonyl),        -   (vii) C₆₋₁₀ aryl-carbonyl (e.g., benzoyl) optionally            substituted by 1 to 3 substituents selected from            -   (i′) halogen atom (e.g., fluorine, chlorine),            -   (ii′) C₁₋₄ alkyl (e.g., methyl, ethyl, isopropyl,                tert-butyl) optionally substituted by 1 to 3                substituents selected from halogen atom (e.g.,                fluorine), cyano, hydroxy and C₃₋₆ cycloalkyl (e.g.,                cyclopropyl),            -   (iii′) C₃₋₆ cycloalkyl (e.g., cyclopropyl, cyclobutyl,                cyclohexyl) optionally substituted by cyano,            -   (iv′) C₁₋₄ alkoxy (e.g., methoxy, ethoxy, isopropoxy,                tert-butoxy) optionally substituted by 1 to 5 halogen                atoms (e.g., fluorine),            -   (v′) C₁₋₄ alkoxy-carbonyl (e.g., methoxycarbonyl), and            -   (vi′) 5- or 6-membered heterocyclic group (e.g.,                tetrahydropyranyl, pyrrolidinyl) optionally substituted                by cyano or oxo,        -   (viii) 5- or 6-membered heterocyclyl-carbonyl containing, as            ring-constituting atom, 1 to 3 heteroatoms selected from            oxygen atom, sulfur atom and nitrogen atom besides carbon            atoms (e.g., furylcarbonyl, tetrahydrofurylcarbonyl,            thienylcarbonyl, pyrrolylcarbonyl, pyrrolidinylcarbonyl,            imidazolylcarbonyl, thiazolylcarbonyl, thiadiazolylcarbonyl,            dihydrooxazolylcarbonyl, oxazolylcarbonyl,            isoxazolylcarbonyl, pyrazolylcarbonyl,            dihydropyrazolylcarbonyl, triazolylcarbonyl,            pyridylcarbonyl, pyrimidinylcarbonyl, pyrazinylcarbonyl)            optionally substituted by 1 to 3 substituents selected from            -   (i′) halogen atom (e.g., chlorine),            -   (ii′) C₁₋₄ alkyl (e.g., methyl, ethyl, isopropyl,                tert-butyl) optionally substituted by 1 to 3                substituents selected from halogen atom (e.g.,                fluorine), cyano, hydroxy and C₁₋₄ alkoxy (e.g.,                methoxy),            -   (iii′) C₆₋₁₀ aryl (e.g., phenyl),            -   (iv′) C₆₋₁₀ aryl-C₁₋₄ alkyl (e.g., benzyl),            -   (v′) C₁₋₄ alkoxy (e.g., methoxy, ethoxy) optionally                substituted by C₁₋₄ alkoxy (e.g., methoxy),            -   (vi′) C₁₋₄ alkylsulfonyl (e.g., methylsulfonyl,                ethylsulfonyl),            -   (vii′) C₁₋₄ alkyl-carbonyl (e.g., acetyl), and            -   (viii′) oxo,        -   (ix) aromatic fused heterocyclyl-carbonyl (e.g.,            benzopyrazolylcarbonyl, indolylcarbonyl),        -   (x) C₁₋₄ alkyl-aminocarbonyl (e.g., ethylaminocarbonyl),        -   (xi) C₆₋₁₀ aryl-aminocarbonyl (e.g., phenylaminocarbonyl)            optionally substituted by C₁₋₄ alkyl (e.g., methyl)            optionally substituted by 1 to 3 halogen atoms (e.g.,            fluorine),        -   (xii) C₁₋₄ alkoxy-aminocarbonyl (e.g., methoxyaminocarbonyl,            isobutoxyaminocarbonyl),        -   (xiii) 5-membered heterocyclyl-aminocarbonyl (e.g.,            isoxazolylaminocarbonyl, pyrazolylaminocarbonyl) optionally            substituted by 1 to 3 substituents selected from C₁₋₄ alkyl            (e.g., methyl, tert-butyl) and C₆₋₁₀ aryl (e.g., phenyl),        -   (xiv) aminothiocarbonyl optionally substituted by C₆₋₁₀            aryl-C₁₋₄ alkyl-carbonyl (e.g., benzylcarbonyl), and        -   (xv) 5-membered aromatic heterocyclyl-sulfonyl (e.g.,            thiazolylsulfonyl) optionally substituted by 1 to 3 C₁₋₄            alkyl (e.g., methyl),    -   (e) C₁₋₄ alkyl-aminocarbonyl (e.g., methylaminocarbonyl)        optionally having C₆₋₁₀ aryl (e.g., phenyl),    -   (f) 5-membered heterocyclyl-aminocarbonyl (e.g.,        pyrazolylaminocarbonyl) optionally substituted by 1 to 3        substituents selected from C₁₋₄ alkyl (e.g., methyl) and C₆₋₁₀        aryl,    -   (g) C₆₋₁₀ aryl-aminocarbonyl (e.g., phenylaminocarbonyl)        optionally substituted by C₁₋₄ alkyl (e.g., methyl, isopropyl,        tert-butyl) optionally substituted by 1 to 3 substituents        selected from halogen atom (e.g., fluorine) and cyano,    -   (h) carboxy, and    -   (i) nitro,        (2) monocyclic aromatic heterocycle (e.g., pyridyl) optionally        substituted by 1 to 3 substituents selected from    -   (a) halogen atom (e.g., bromine), and    -   (b) C₆₋₁₀ aryl-carbonylamino (e.g., benzoylamino) optionally        substituted by C₁₋₄ alkyl (e.g., methyl) optionally substituted        by 1 to 3 halogen atoms (e.g., fluorine), or        (3) fused aromatic heterocycle (e.g., indolyl, benzothiazolyl,        benzimidazolyl) optionally substituted by 1 to 3 substituents        selected from    -   (a) C₁₋₄ alkyl (e.g., methyl), and,    -   (b) C₆₋₁₀ arylamino (e.g., phenylamino) optionally substituted        by C₁₋₄ alkyl (e.g., methyl) optionally substituted by 1 to 3        halogen atoms (e.g., fluorine).

As ring Ya, (1,3-dimethyl-1H-pyrazol-5-yl)aminocarbonyl-3-phenyl,3-aminophenyl, 4-aminophenyl, 3-{[(ethylamino)carbonyl]amino}phenyl,4-{[(phenylamino)carbonyl]amino}phenyl,3-{[(phenylamino)carbonyl]amino}phenyl,3-({[3-(trifluoromethylphenyl)amino]carbonyl}amino)phenyl,3-({[4-(trifluoromethylphenyl)amino]carbonyl}amino)phenyl,3-[(tert-butylcarbonyl)amino]phenyl,3-[(cyclopropylcarbonyl)amino]phenyl,3-[(cyclohexylcarbonyl)amino]phenyl, 3-[(phenylcarbonyl)amino]phenyl,3-{[3-(trifluoromethylphenyl)carbonyl]amino}phenyl,3-{[3-(fluorophenyl)carbonyl]amino}phenyl,3-{[3-(chlorophenyl)carbonyl]amino}phenyl,3-{[3-(pyridyl)carbonyl]amino}phenyl,3-{[2-(furyl)carbonyl]amino}phenyl,3-{[3-(2,5-dimethylfuran)carbonyl]amino}phenyl,3-{[2-(3-methylthiophene)carbonyl]amino}phenyl,3-{[5-(4-methyl-1,2,3-thiadiazole)carbonyl]amino}phenyl,3-{[5-(isoxazole)carbonyl]amino}phenyl,3-{[5-(1,3-dimethyl-1H-pyrazole)carbonyl]amino}phenyl,3-{[5-(3-methylisoxazole)carbonyl]amino}phenyl,3-{[3-(5-methylisoxazole)carbonyl]amino}phenyl,3-({5-[1-methyl-3-(trifluoromethyl)-1H-pyrazole]carbonyl}amino)phenyl,5-methyl-2-(trifluoromethyl)-3-furancarbonylaminophenyl,3-{[5-(2,4-dimethyl-1,3-thiazole)carbonyl]amino}phenyl,3-{[4-(2,5-dimethyl-1,3-oxazole)carbonyl]amino}phenyl,3-{[5-(1-methyl-1H-pyrazole)carbonyl]amino}phenyl,3-{[3-(1,5-dimethyl-1H-pyrazole)carbonyl]amino}phenyl,3-{[4-(3,5-dimethylisoxazole)carbonyl]amino}phenyl,3-{[5-(1-methyl-1H-1,2,3-triazole)carbonyl]amino}phenyl,3-{[4-(1-methyl-1H-1,2,3-triazole)carbonyl]amino}phenyl,3-{[2-(1-methyl-1H-imidazole)carbonyl]amino}phenyl,3-{[5-(1-methyl-1H-imidazole)carbonyl]amino}phenyl, 1H-indol-6-yl,2-methyl-1H-indol-6-yl, 1,2-dimethyl-1H-benzimidazol-5-yl,1H-indol-4-yl, 2-methyl-1,3-benzothiazol-5-yl,2-methyl-1,3-benzothiazol-6-yl, 5-amino-2-methylphenyl,3-amino-2-methylphenyl, 3-amino-4-methylphenyl, 3-amino-4-chlorophenyl,5-amino-2-chlorophenyl, 5-amino-2-methoxyphenyl,6-methyl-3-{[5-(1,3-dimethyl-1H-pyrazole)carbonyl]amino}phenyl,2-methyl-3-{[5-(1,3-dimethyl-1H-pyrazole)carbonyl]amino}phenyl,4-methyl-3-{[5-(1,3-dimethyl-1H-pyrazole)carbonyl]amino}phenyl,4-chloro-3-{[5-(1,3-dimethyl-1H-pyrazole)carbonyl]amino}phenyl,6-chloro-3-{[5-(1,3-dimethyl-1H-pyrazole)carbonyl]amino}phenyl,4-fluoro-3-{[5-(1,3-dimethyl-1H-pyrazole)carbonyl]amino}phenyl,6-methoxy-3-{[5-(1,3-dimethyl-1H-pyrazole)carbonyl]amino}phenyl,4-chloro-3-(cyclopropylcarbonylamino)phenyl, 3-amino-4-fluorophenyl,4-fluoro-3-{[4-(1-ethyl-3-methyl-1H-pyrazole)carbonyl]amino}phenyl andthe like can be specifically mentioned.

In the compound (II), as the substituent for R^(a) of NR^(a) defined byXa, those similar to the substituent selected from the group exemplifiedas the “optionally substituted hydrocarbon group” for the aforementionedSubstituent Group (1)(iv), the group exemplified as the “optionallysubstituted aminocarbonyl” for the aforementioned Substituent Group(1)(viii), the group exemplified as the “acyl” for the aforementionedSubstituent Group (1)(ix) and the group exemplified as the “optionallysubstituted heterocyclic group” for the aforementioned Substituent Group(1)(xii) can be mentioned.

As the substituent for R^(a), optionally substituted hydrocarbon groupand the like are preferable.

Xa is preferably —O—, —S— or —NH—, more preferably —O— or —S—, andparticularly preferably —O—.

As the “optionally substituted amino” for R^(1a) in the compound (II),those similar to the “optionally substituted amino” exemplified in theaforementioned Substituent Group (1)(x) can be mentioned.

As the “optionally substituted amino” for R^(1a), (1) amino, (2)optionally substituted alkylcarbonylamino, (3) optionally substitutedalkenylcarbonylamino, (4) optionally substituted alkynylcarbonylamino,(5) optionally substituted cycloalkylcarbonylamino, (6) optionallysubstituted cycloalkyl-alkylcarbonylamino, (7) optionally substituted6-membered heterocyclyl-carbonylamino, (8) optionally substitutedaminocarbonylamino, (9) optionally substituted alkoxycarbonylamino, (10)optionally substituted alkylsulfonylamino, (11) optionally substitutedcycloalkylsulfonylamino, (12) optionally substituted arylamino and (13)optionally substituted heterocyclylamino are preferable.

Of these, preferable R^(1a) are

(1) amino,

(2) C₁₋₄ alkyl-carbonylamino (e.g., acetylamino, ethylcarbonylamino,isopropylcarbonylamino, isobutylcarbonylamino, tert-butylcarbonylamino)optionally substituted by 1 to 3 substituents selected from (a) halogenatom (e.g., chlorine), (b) hydroxy, (c) C₁₋₄ alkoxy (e.g., methoxy), (d)C₁₋₄ alkyl-carbonyloxy (e.g., methylcarbonyloxy), (e) C₁₋₄ alkylamino(e.g., methylamino), (f) di-C₁₋₄ alkylamino (e.g., dimethylamino), (g)C₁₋₄ alkylsulfonyl (e.g., methylsulfonyl), and (h) 6-memberedheterocyclic group (e.g., piperazinyl, morpholinyl) optionallysubstituted by 1 to 3 C₁₋₄ alkyl (e.g., methyl),(3) C₂₋₄ alkenyl-carbonylamino (e.g., vinylcarbonylamino,2-methyl-1-propenylcarbonylamino) optionally having C₁₋₄ alkoxy (e.g.,methoxy),(4) C₂₋₄ alkynyl-carbonylamino (e.g., 1-propenylcarbonylamino),(5) C₃₋₆ cycloalkyl-carbonylamino (e.g., cyclopropylcarbonylamino,cyclobutylcarbonylamino, cyclopentylcarbonylamino,cyclohexylcarbonylamino) optionally substituted by 1 to 4 substituentsselected from (a) halogen atom (e.g., fluorine), (b) hydroxy, (c) C₁₋₄alkyl (e.g., methyl, isopropyl) optionally having hydroxy, (d) C₁₋₄alkoxy (e.g., methoxy), (e) C₁₋₄ alkoxy-carbonyl (e.g.,methoxycarbonyl), and (f) C₁₋₄ alkyl-carbonyloxy (e.g., acetoxy),(6) C₃₋₆ cycloalkyl-C₁₋₄ alkyl-carbonylamino (e.g.,cyclopropylmethylcarbonylamino),(7) 6-membered heterocyclyl-carbonylamino (e.g.,tetrahydropyranylcarbonylamino, pyridylcarbonylamino,pyrimidinylcarbonylamino, morpholinylcarbonylamino) optionallysubstituted by 1 to 3 substituents selected from (a) halogen atom (e.g.,fluorine, chlorine), (b) cyano, and (c) C₁₋₄ alkyl (e.g., methyl)optionally having 1 to 3 halogen atom (e.g., fluorine),(8) aminocarbonylamino optionally substituted by 1 or 2 substituentsselected from (a) C₁₋₄ alkyl (e.g., ethyl) optionally having 1 to 3 C₁₋₄alkoxy (e.g., ethoxy) optionally having 1 to 3 hydroxy, and (b) C₁₋₄alkoxy (e.g., methoxy),(9) C₁₋₄ alkoxy-carbonylamino (e.g., methoxycarbonylamino,ethoxycarbonylamino, tert-butoxycarbonylamino) optionally substituted by1 to 3 halogen atom (e.g., chlorine),(10) C₁₋₄ alkylsulfonylamino (e.g., methylsulfonylamino),(11) C₃₋₆ cycloalkylsulfonylamino (e.g., cyclopropylsulfonylamino),(12) C₆₋₁₀ arylamino (e.g., phenylamino), and(13) heterocyclylamino (e.g., thiazolylamino, pyrimidinylamino)optionally substituted by 1 to 3 substituents selected from (a) halogenatom (e.g., chlorine), and (b) C₁₋₄ alkylamino (e.g., methylamino), andthe like.

As R^(1a), amino, acetylamino, chloroacetylamino,4-morpholinylacetylamino, methylcarbonyloxymethylcarbonylamino,methylaminomethylcarbonylamino, hydroxymethylcarbonylamino,methoxymethylcarbonylamino, ethylcarbonylamino, isopropylcarbonylamino,dimethylaminomethylcarbonylamino, 4-methylpiperazin-1-ylacetylamino,methylsulfonylmethylcarbonylamino, 3-hydroxy-3-methylbutanoylamino,hydroxyethylcarbonylamino, 3-methyl-2-butenoylamino,3-methoxy-2-propenoylamino, 2-butynoylamino, (cyclopropylcarbonyl)amino,(1-methoxycarbonylcyclopropylcarbonyl)amino,(1-hydroxycyclopropylcarbonyl)amino, (2-methylcyclopropylcarbonyl)amino,(2-methoxycyclopropylcarbonyl)amino,(2-methylcarbonylcyclopropylcarbonyl)amino,(2-hydroxymethylcarbonylcyclopropylcarbonyl)amino,(2-(1-hydroxy-1-methylethyl)cyclopropyl)carbonylamino,(2,2-dimethylcyclopropylcarbonyl)amino,(2,2-difluorocyclopropylcarbonyl)amino,(2,2,3,3-tetramethylcyclopropylcarbonyl)amino,(cyclobutylcarbonyl)amino, (cyclopentylcarbonyl)amino,(cyclohexylcarbonyl)amino, cyclopropylmethylcarbonylamino,(tetrahydro-2H-pyran-4-ylcarbonyl)amino, (3-pyridylcarbonyl)amino,(4-pyridylcarbonyl)amino, (6-methyl-3-pyridylcarbonyl)amino,(6-fluoro-3-pyridylcarbonyl)amino, (6-chloro-3-pyridylcarbonyl)amino,(6-cyano-3-pyridylcarbonyl)amino,(6-(trifluoromethyl)-3-pyridylcarbonyl)amino,(5-pyrimidinylcarbonyl)amino, 4-morpholinylcarbonylamino, methoxyureido,ethylureido, 2-hydroxyethoxyethylureido, methoxycarbonylamino,ethoxycarbonylamino, 2,2,2-trichloroethoxycarbonylamino,tert-butoxycarbonylamino, methylsulfonylamino,(cyclopropylsulfonyl)amino, phenylamino,2-methylaminopyrimidin-4-ylamino, 2-chloropyrimidin-4-ylamino,1,3-thiazol-2-ylamino and the like can be specifically mentioned.

In the compound (II), as the “substituent” for R^(2a), those similar tothe substituents of the aforementioned Substituent Group (1) can bementioned.

Of these, preferable R^(2a) is hydrogen atom.

In the compound (II), as the “substituent” for R^(3a), those similar tothe substituents of the aforementioned Substituent Group (1) can bementioned.

Of these, preferable R^(3a) is hydrogen atom.

In the compound (II), as the “substituent” for R^(4a), those similar tothe substituents of the aforementioned Substituent Group (1) can bementioned.

Of these, preferable R^(4a) is hydrogen atom.

As preferable examples of the compound (II), for example, the followingcompounds can be mentioned.

A compound wherein

ring Ya is

(1) C₆₋₁₀ aryl optionally substituted by 1 to 3 substituents selectedfrom

-   -   (a) halogen atom,    -   (b) C₁₋₄ alkyl,    -   (c) C₁₋₄ alkoxy,    -   (d) amino optionally substituted by the substituents selected        from        -   (i) C₁₋₄ alkyl optionally substituted by a 5-membered            aromatic heterocyclic group optionally substituted by 1 to 3            C₁₋₄ alkyl,        -   (ii) C₁₋₄ alkyl-carbonyl optionally substituted by 1 to 3            substituents selected from            -   (i′) hydroxy,            -   (ii′) C₁₋₄ alkylsulfonyl, and            -   (iii′) 6-membered aromatic heterocyclic group,        -   (iii) C₂₋₄ alkenyl-carbonyl optionally substituted by C₆₋₁₀            aryl,        -   (iv) C₂₋₄ alkynyl-carbonyl optionally substituted by C₆₋₁₀            aryl,        -   (v) C₃₋₆ cycloalkyl-carbonyl,        -   (vi) C₃₋₆ cycloalkenyl-carbonyl,        -   (vii) C₆₋₁₀ aryl-carbonyl optionally substituted by 1 to 3            substituents selected from            -   (i′) halogen atom,            -   (ii′) C₁₋₄ alkyl optionally substituted by 1 to 3                substituents selected from halogen atom, cyano, hydroxy                and C₃₋₆ cycloalkyl,            -   (iii′) C₃₋₆ cycloalkyl optionally substituted by cyano,            -   (iv′) C₁₋₄ alkoxy optionally substituted by 1 to 5                halogen atoms,            -   (v′) C₁₋₄ alkoxy-carbonyl, and            -   (vi′) 5- or 6-membered heterocyclic group optionally                substituted by cyano or oxo,        -   (viii) 5- or 6-membered heterocyclyl-carbonyl containing, as            ring-constituting atom, 1 to 3 heteroatoms selected from            oxygen atom, sulfur atom and nitrogen atom besides carbon            atoms, which is optionally substituted by 1 to 3            substituents selected from            -   (i′) halogen atom,            -   (ii′) C₁₋₄ alkyl optionally substituted by 1 to 3                substituents selected from halogen atom, cyano, hydroxy                and C₁₋₄ alkoxy,            -   (iii′) C₆₋₁₀ aryl,            -   (iv′) C₆₋₁₀ aryl-C₁₋₄ alkyl,            -   (v′) C₁₋₄ alkoxy optionally substituted by C₁₋₄ alkoxy,            -   (vi′) C₁₋₄ alkylsulfonyl,            -   (vii′) C₁₋₄ alkyl-carbonyl, and            -   (viii′) oxo,        -   (ix) aromatic fused heterocyclyl-carbonyl,        -   (x) C₁₋₄ alkyl-aminocarbonyl,        -   (xi) C₆₋₁₀ aryl-aminocarbonyl optionally substituted by C₁₋₄            alkyl optionally substituted by 1 to 3 halogen atoms,        -   (xii) C₁₋₄ alkoxy-aminocarbonyl,        -   (xiii) 5-membered heterocyclyl-aminocarbonyl optionally            substituted by 1 to 3 substituents selected from C₁₋₄ alkyl            and C₆₋₁₀ aryl,        -   (xiv) aminothiocarbonyl optionally substituted by C₆₋₁₀            aryl-C₁₋₄ alkyl-carbonyl, and        -   (xv) 5-membered aromatic heterocyclyl-sulfonyl optionally            substituted by 1 to 3 C₁₋₄ alkyl,    -   (e) C₁₋₄ alkyl-aminocarbonyl optionally having C₆₋₁₀ aryl,    -   (f) 5-membered heterocyclyl-aminocarbonyl optionally substituted        by 1 to 3 substituents selected from C₁₋₄ alkyl and C₆₋₁₀ aryl,    -   (g) C₆₋₁₀ aryl-aminocarbonyl optionally substituted by C₁₋₄        alkyl optionally substituted by 1 to 3 substituents selected        from halogen atom and cyano,    -   (h) carboxy, and    -   (i) nitro,        (2) monocyclic aromatic heterocycle optionally substituted by 1        to 3 substituents selected from    -   (a) halogen, and    -   (b) C₆₋₁₀ aryl-carbonylamino optionally substituted by C₁₋₄        alkyl optionally substituted by 1 to 3 halogen atoms, or        (3) fused aromatic heterocycle optionally substituted by 1 to 3        substituents selected from    -   (a) C₁₋₄ alkyl, and    -   (b) C₆₋₁₀ arylamino optionally substituted by C₁₋₄ alkyl        optionally substituted by 1 to 3 halogen atoms;        Xa is —O—, —S— or —NH— (more preferably —O— or —S—, particularly        preferably —O—);        R^(1a) is        (1) amino,        (2) C₁₋₄ alkyl-carbonylamino optionally substituted by 1 to 3        substituents selected from    -   (a) halogen atom,    -   (b) hydroxy,    -   (c) C₁₋₄ alkoxy,    -   (d) C₁₋₄ alkyl-carbonyloxy,    -   (e) C₁₋₄ alkylamino,    -   (f) di-C₁₋₄ alkylamino,    -   (g) C₁₋₄ alkylsulfonyl, and    -   (h) 6-membered heterocyclic group optionally having 1 to 3 C₁₋₄        alkyl,        (3) C₂₋₄ alkenyl-carbonylamino optionally having C₁₋₄ alkoxy,        (4) C₂₋₄ alkynyl-carbonylamino,        (5) C₃₋₆ cycloalkyl-carbonylamino optionally substituted by 1 to        4 substituents selected from    -   (a) halogen atom,    -   (b) hydroxy,    -   (c) C₁₋₄ alkyl optionally having hydroxy,    -   (d) C₁₋₄ alkoxy, and    -   (e) C₁₋₄ alkoxy-carbonyl,        (6) C₃₋₆ cycloalkyl-C₁₋₄ alkyl-carbonylamino,        (7) 6-membered heterocyclyl-carbonylamino optionally substituted        by 1 to 3 substituents selected from    -   (a) halogen atom,    -   (b) cyano, and    -   (c) C₁₋₄ alkyl optionally having 1 to 3 halogen atoms,        (8) aminocarbonylamino optionally substituted by 1 or 2        substituents selected from    -   (a) C₁₋₄ alkyl optionally having 1 to 3 C₁₋₄ alkoxy optionally        having 1 to 3 hydroxy, and    -   (b) C₁₋₄ alkoxy,        (9) C₁₋₄ alkoxy-carbonylamino optionally substituted by 1 to 3        halogen atoms,        (10) C₁₋₄ alkylsulfonylamino,        (11) C₃₋₆ cycloalkylsulfonylamino,        (12) C₆₋₁₀ arylamino, and        (13) heterocyclylamino optionally substituted by 1 to 3        substituents selected from    -   (a) halogen atom, and    -   (b) C₁₋₄ alkylamino; and        R^(2a), R^(3a) and R^(4a) are each hydrogen atom.

As the specific examples of the compound (II), for example, compounds ofExamples 1 to 60, 64, 66 to 72, 74 to 123, 126 to 138 and 147 to 439 canbe mentioned.

Of these, the following compounds or salts thereof are preferable.

-   N-{3-[(2-{[2-(methylamino)pyrimidin-4-yl]amino}imidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide    (Example 70);-   N-[2-chloro-5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide    (Example 97);-   N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide    (Example 111);-   N-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-2,4-dimethyl-1,3-thiazole-5-carboxamide    (Example 114);-   N-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-2,5-dimethyl-1,3-oxazole-4-carboxamide    (Example 117);-   N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide    (Example 148);-   N-[3-({2-[(N,N-dimethylglycyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide    (Example 149);-   N-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}sulfanyl)phenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide    (Example 150);-   N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-1-ethyl-3-methyl-1H-pyrazole-4-carboxamide    (Example 161);-   N-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]benzamide    (Example 165);-   N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-1,3-dimethyl-1H-pyrazole-4-carboxamide    (Example 173);-   N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-1-ethyl-1H-pyrazole-5-carboxamide    (Example 174);-   N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-3-methoxy-1-methyl-1H-pyrazole-5-carboxamide    (Example 180);-   N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-3-ethyl-1-methyl-1H-pyrazole-5-carboxamide    (Example 208);-   N-[2-chloro-5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-1-ethyl-3-methyl-1H-pyrazole-4-carboxamide    (Example 254);-   N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-1-methyl-1H-pyrazole-5-carboxamide    (Example 287);-   N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-2,4-dimethyl-1,3-oxazole-5-carboxamide    (Example 289);-   N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-2-ethyl-4-methyl-1,3-oxazole-5-carboxamide    (Example 314);-   N-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-3-(trifluoromethyl)benzamide    (Example 319);-   3-(1-cyano-1-methylethyl)-N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]benzamide    (Example 330);-   N-[3-({2-[(N,N-dimethylglycyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-3-(trifluoromethyl)benzamide    (Example 398);-   N-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}thio)phenyl]-3-(trifluoromethyl)benzamide    (Example 427);-   N-{6-[3-({[3-(trifluoromethyl)phenyl]carbamoyl}amino)phenoxy]imidazo[1,2-b]pyridazin-2-yl}cyclopropanecarboxamide    (Example 431).

The compound represented by the formula (III) (hereinafter compound(III)) of the present invention is explained below.

As the “cyclic group” of the “cyclic group substituted by an optionallysubstituted amino, wherein the cyclic group is optionally furthersubstituted”, for ring Yb, those similar to the groups exemplified asthe “cyclic group” of the “optionally substituted cyclic group” for ringY of compound (I) can be mentioned.

As the “cyclic group” of the “cyclic group substituted by an optionallysubstituted amino, wherein the cyclic group is optionally furthersubstituted” for ring Yb, aromatic hydrocarbon group, aromaticheterocyclic group are preferable. As the aromatic hydrocarbon group,C₆₋₁₄ aryl is preferable, C₆₋₁₀ aryl is more preferable, and phenyl isparticularly preferable. As the aromatic heterocyclic group, fusedaromatic heterocyclic group is preferable, fused aromatic heterocyclicgroup formed by fusion of 5-membered monocyclic aromatic heterocyclicgroup containing, as ring-constituting atom, 1 or 2 heteroatoms selectedfrom sulfur atom and nitrogen atom, besides carbon atoms, and benzenering (e.g., benzothiazolyl, benzimidazolyl, indolyl etc.) is morepreferable, and benzothiazolyl (e.g., 5-benzothiazolyl,6-benzothiazolyl), benzimidazolyl (e.g., benzimidazol-5-yl,benzimidazol-6-yl), indolyl (e.g., indol-4-yl, indol-5-yl, indol-6-yl)and the like are particularly preferable.

The “cyclic group substituted by an optionally substituted amino,wherein the cyclic group is optionally further substituted” for ring Ybis substituted, at its any substitutable position, by optionallysubstituted amino that may further have 1 to the acceptable maximumnumber, preferably 1 to 5, more preferably 1 to 3, substituents at anysubstitutable position(s). Where the cyclic group is substituted by twoor more substituents, the substituents may be the same or different.

As the “optionally substituted amino” of the “cyclic group substitutedby an optionally substituted amino, wherein the cyclic group isoptionally further substituted” for ring Yb, those similar to the groupexemplified as the “optionally substituted amino” (Substituent Group(1)(x)) among the groups exemplified as the “substituent” of the“optionally substituted cyclic group” for ring Y of compound (I). As thesubstituent that may be used for the further substitution, those similarto the group exemplified as the “substituent” of the “optionallysubstituted cyclic group” for ring Y of compound (I) can be mentioned.

As the “substituent” of the “optionally substituted amino” in the“cyclic group substituted by an optionally substituted amino, whereinthe cyclic group is optionally further substituted” for ring Yb, the“optionally substituted aminocarbonyl” of the aforementioned SubstituentGroup (1)(viii), and the “acyl” of the aforementioned Substituent Group(1)(ix) are preferable among the substituents referenced and exemplifiedabove. Of these, (1) C₆₋₁₈ aryl-aminocarbonyl (e.g., phenylaminocarbonyletc.) optionally substituted by C₁₋₄ alkyl (e.g., methyl) optionallyhaving halogen atom (e.g., fluorine) (specific examples:phenylaminocarbonyl, 3-trifluoromethylphenylaminocarbonyl,4-trifluoromethylphenylaminocarbonyl etc.), (2) C₆₋₁₈ aryl-carbonyl(e.g., phenylcarbonyl etc.) optionally substituted by C₁₋₄ alkyl (e.g.,methyl) optionally having halogen atom (e.g., fluorine) (specificexamples: phenylcarbonyl, 3-trifluoromethylphenylcarbonyl etc.) and (3)5- or 6-membered monocyclic aromatic heterocycle (e.g., pyrazolyletc.)-carbonyl containing, as ring-constituting atom, 1 to 3 heteroatomsselected from oxygen atom, sulfur atom and nitrogen atom besides carbonatoms, which is optionally substituted by C₁₋₄ alkyl (e.g., methyl) andthe like (specific examples: 1,3-dimethyl-1H-pyrazole-5-carbonyl etc.),and the like are preferable.

Of the substituents referenced and exemplified above, the “substituent”by which the “cyclic group” is optionally substituted is preferably

(1) halogen atom (e.g., fluorine, chlorine, bromine, iodine),

(2) optionally substituted alkyl,

(3) optionally substituted alkoxy,

(4) optionally substituted aminocarbonyl,

(5) optionally substituted amino,

and the like.

Of these,

(1) halogen atom (e.g., fluorine, chlorine, bromine, iodine),

(2) optionally substituted alkyl,

(3) optionally substituted amino,

and the like are preferable.

Hereinafter the above-mentioned preferable examples of the substituentby which the cyclic group is further substituted of the “cyclic groupsubstituted by an optionally substituted amino, wherein the cyclic groupis optionally further substituted” for ring Yb are exemplified indetail.

(1) As the halogen atom, fluorine, chlorine, bromine and the like arepreferable.

(2) As the optionally substituted alkyl, optionally substituted C₁₋₈alkyl is preferable, optionally substituted C₁₋₄ alkyl is morepreferable, and unsubstituted C₁₋₄ alkyl is much more preferable.Specifically, methyl, ethyl and the like are preferable.

(3) As the optionally substituted alkoxy, optionally substituted C₁₋₈alkoxy is preferable, optionally substituted C₁₋₄ alkoxy is morepreferable, and unsubstituted C₁₋₄ alkoxy is more preferable.Specifically methoxy and the like are preferable.

(4) As the “substituent” for the optionally substituted aminocarbonyl,for example, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₈ cycloalkyl,C₃₋₈ cycloalkenyl, C₃₋₈ cycloalkynyl, C₆₋₁₈ aryl, heterocyclic group andthe like, each of which is optionally substituted, are preferable,optionally substituted heterocyclic group and the like are morepreferable, and optionally substituted aromatic heterocyclic group isparticularly preferable. As the optionally substituted aminocarbonyl,aminocarbonyl optionally substituted by aromatic heterocyclic groupoptionally substituted C₁₋₄ alkyl and the like are preferable, and1,3-dimethyl-1H-pyrazol-5-yl-aminocarbonyl and the like are specificallypreferable.(5) As the “substituent” for the optionally substituted amino,optionally substituted aminocarbonyl, acyl and the like are preferable.

As the optionally substituted amino, unsubstituted amino; aminooptionally substituted by optionally substituted aminocarbonyl; aminooptionally substituted by acyl and the like are preferable.

As the optionally substituted aminocarbonyl, C₁₋₈ alkyl-aminocarbonyl,C₆₋₁₈ aryl-aminocarbonyl, C₆₋₁₈ aryl-C₁₋₄ alkyl-aminocarbonyl,heterocyclyl-aminocarbonyl, C₃₋₈ cycloalkyl-aminocarbonyl and the like,each of which is optionally substituted, are preferable. Of these,optionally substituted C₁₋₈ alkyl-aminocarbonyl and the like arepreferable, and optionally substituted C₁₋₄ alkyl-aminocarbonyl is morepreferable. Specifically, ethylaminocarbonyl and the like arepreferable. Alternatively, optionally substituted C₆₋₁₈aryl-aminocarbonyl and the like are preferable, optionally substitutedC₆₋₁₀ aryl-aminocarbonyl is more preferable, and those wherein the arylmoiety is unsubstituted phenyl; phenyl optionally substituted by halogenatom (e.g., fluorine, chlorine), optionally halogenated C₁₋₄ alkyl(e.g., trifluoromethyl) and the like, and the like are particularlypreferable. Specifically, phenylaminocarbonyl (anilinocarbonyl),3-trifluoromethylphenylaminocarbonyl (3-trifluoromethylanilinocarbonyl),4-trifluoromethylphenylaminocarbonyl (4-trifluoromethylanilinocarbonyl)and the like are preferable.

As the acyl, C₁₋₈ alkyl-carbonyl, C₆₋₁₈ aryl-carbonyl, C₆₋₁₈ aryl-C₁₋₄alkyl-carbonyl, C₁₋₈ alkylsulfonyl, C₆₋₁₈ aryl-sulfonyl,heterocyclyl-carbonyl, heterocyclyl-sulfonyl, C₃₋₈ cycloalkyl-carbonyland the like, each of which is optionally substituted, are preferable.Of these, C₁₋₈ alkyl-carbonyl, C₃₋₈ cycloalkyl-carbonyl, C₆₋₁₈aryl-carbonyl, heterocyclyl-carbonyl, each of which is optionallysubstituted, are preferable.

As the optionally substituted C₁₋₈ alkyl-carbonyl, C₁₋₄ alkyl-carbonylis preferable, and tert-butylcarbonyl and the like are specificallypreferable.

As the optionally substituted C₃₋₈ cycloalkyl-carbonyl, C₃₋₆cycloalkyl-carbonyl is preferable, and cyclopropylcarbonyl,cyclohexylcarbonyl and the like are specifically preferable.

As the optionally substituted C₆₋₁₈ aryl-carbonyl, optionallysubstituted C₆₋₁₀ aryl-carbonyl is preferable, and optionallysubstituted phenyl-carbonyl is more preferable. As the “substituent” forthe optionally substituted C₆₋₁₈ aryl-carbonyl, halogen atom (e.g.,fluorine, chlorine), optionally halogenated C₁₋₄ alkyl (e.g.,trifluoromethyl) and the like are preferable. As the optionallysubstituted C₆₋₁₈ aryl-carbonyl, those wherein the “aryl” moiety isunsubstituted phenyl; phenyl optionally substituted by halogen atom(e.g., fluorine, chlorine), optionally halogenated C₁₋₄ alkyl (e.g.,trifluoromethyl) and the like, and the like are preferable.Specifically, phenylcarbonyl(benzoyl), 3-trifluoromethylphenylcarbonyl,3-fluorophenylcarbonyl, 3-chlorophenylcarbonyl and the like arepreferable.

As the “heterocycle” moiety for the optionally substitutedheterocyclyl-carbonyl, 5- or 6-membered monocyclic aromatic heterocyclicgroup containing, as ring-constituting atom, 1 to 3 heteroatoms selectedfrom oxygen atom, sulfur atom and nitrogen atom besides carbon atoms andthe like are preferable, and pyridyl, furyl, thienyl, pyrazolyl,imidazolyl, thiazolyl, oxazolyl, isoxazolyl, 1,2,3-triazolyl,1,2,3-thiadiazolyl, pyridazinyl and the like are specificallypreferable. As the “substituent” for the optionally substitutedheterocyclyl-carbonyl, optionally halogenated C₁₋₄ alkyl (e.g., methyl,trifluoromethyl) and the like are preferable.

As the optionally substituted heterocyclyl-carbonyl, the above-mentioned5- or 6-membered monocyclic aromatic heterocyclyl-carbonyl and the likeoptionally substituted by optionally halogenated C₁₋₄ alkyl and the likeare preferable. specifically, 3-pyridylcarbonyl, 2-furylcarbonyl,2,5-dimethylfuran-3-carbonyl, 3-methylthiophene-2-carbonyl,4-methyl-1,2,3-thiadiazole-5-carbonyl, isoxazole-5-carbonyl,1,3-dimethyl-1H-pyrazole-5-carbonyl, 3-methylisoxazole-5-carbonyl,5-methylisoxazole-3-carbonyl,1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-carbonyl,5-methyl-2-(trifluoromethyl)-3-furancarbonyl,2,4-dimethyl-1,3-thiazole-5-carbonyl,2,5-dimethyl-1,3-oxazole-4-carbonyl, 1-methyl-1H-pyrazole-5-carbonyl,1,5-dimethyl-1H-pyrazole-3-carbonyl, 3,5-dimethylisoxazole-4-carbonyl,1-methyl-1H-1,2,3-triazole-5-carbonyl,1-methyl-1H-1,2,3-triazole-4-carbonyl, 1-methyl-1H-imidazole-2-carbonyl,1-methyl-1H-imidazole-5-carbonyl and the like are preferable.

Preferably, ring Yb is

(1) C₆₋₁₄ aryl (e.g., phenyl etc.) substituted by amino optionallysubstituted by substituent selected from (1′) C₆₋₁₈ aryl-aminocarbonyl(e.g., phenylaminocarbonyl etc.) optionally substituted by C₁₋₄ alkyl(e.g., methyl) optionally having halogen atom (e.g., fluorine) (specificexamples: phenylaminocarbonyl, 3-trifluoromethylphenylaminocarbonyl,4-trifluoromethylphenylaminocarbonyl etc.), (2′) C₆₋₁₈ aryl-carbonyl(e.g., phenylcarbonyl etc.) optionally substituted by C₁₋₄ alkyl (e.g.,methyl) optionally having halogen atom (e.g., fluorine) (specificexamples: phenylcarbonyl, 3-trifluoromethylphenylcarbonyl etc.), and(3′) 5- or 6-membered monocyclic aromatic heterocycle (e.g., pyrazolyletc.)-carbonyl containing, as ring-constituting atom, 1 to 3 heteroatomsselected from oxygen atom, sulfur atom and nitrogen atom besides carbonatoms, which is optionally substituted by C₁₋₄ alkyl (e.g., methyl) andthe like (specific examples: 1,3-dimethyl-1H-pyrazole-5-carbonyl etc.),wherein said C₆₋₁₄ aryl is optionally further substituted by 1 or 2substituents selected from

-   -   (i) halogen atom (e.g., fluorine, chlorine, bromine, iodine        etc.),    -   (ii) C₁₋₄ alkyl (e.g., methyl etc.),    -   (iii) C₁₋₄ alkoxy (e.g., methoxy etc.),    -   (iv) aminocarbonyl substituted by aromatic heterocyclic group        (e.g., pyrazolyl etc.) optionally substituted by C₁₋₄ alkyl        (e.g., methyl etc.), and    -   (v) amino optionally substituted by substituent selected from        -   (a) C₁₋₄ alkyl-carbonyl (e.g., tert-butylcarbonyl etc.),        -   (b) C₃₋₆ cycloalkyl-carbonyl (e.g., cyclopropylcarbonyl,            cyclohexylcarbonyl etc.),        -   (c) C₆₋₁₈ aryl-carbonyl (e.g., phenylcarbonyl etc.)            optionally substituted by substituent selected from halogen            atom (e.g., fluorine, chlorine) and optionally halogenated            C₁₋₄ alkyl (e.g., trifluoromethyl) (specific examples:            phenylcarbonyl (benzoyl), 3-trifluoromethylphenylcarbonyl,            3-fluorophenylcarbonyl, 3-chlorophenylcarbonyl etc.), and        -   (d) 5- or 6-membered monocyclic aromatic heterocyclic group            (e.g., pyridyl, furyl, thienyl, pyrazolyl, imidazolyl,            thiazolyl, oxazolyl, isoxazolyl, 1,2,3-triazolyl,            1,2,3-thiadiazolyl, pyridazinyl etc.)-carbonyl containing,            as ring-constituting atom, 1 to 3 heteroatoms selected from            oxygen atom, sulfur atom and nitrogen atom besides carbon            atoms, which is optionally substituted by C₁₋₄ alkyl (e.g.,            methyl) optionally having halogen atom (e.g., fluorine) and            the like (specific examples: 3-pyridylcarbonyl,            2-furylcarbonyl, 2,5-dimethylfuran-3-carbonyl,            3-methylthiophene-2-carbonyl,            4-methyl-1,2,3-thiadiazole-5-carbonyl, isoxazole-5-carbonyl,            1,3-dimethyl-1H-pyrazole-5-carbonyl,            3-methylisoxazole-5-carbonyl, 5-methylisoxazole-3-carbonyl,            1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-carbonyl,            5-methyl-2-(trifluoromethyl)-3-furancarbonyl,            2,4-dimethyl-1,3-thiazole-5-carbonyl,            2,5-dimethyl-1,3-oxazole-4-carbonyl,            1-methyl-1H-pyrazole-5-carbonyl,            1,5-dimethyl-1H-pyrazole-3-carbonyl,            3,5-dimethylisoxazole-4-carbonyl,            1-methyl-1H-1,2,3-triazole-5-carbonyl,            1-methyl-1H-1,2,3-triazole-4-carbonyl,            1-methyl-1H-imidazole-2-carbonyl,            1-methyl-1H-imidazole-5-carbonyl etc.),    -   and the like,        (2) fused aromatic heterocycle (e.g., benzothiazolyl (e.g.,        5-benzothiazolyl, 6-benzothiazolyl), benzimidazolyl (e.g.,        benzimidazol-5-yl, benzimidazol-6-yl), indolyl (e.g.,        indol-4-yl, indol-5-yl, indol-6-yl) etc.) substituted by amino        optionally substituted by (1′) C₆₋₁₈ aryl-aminocarbonyl (e.g.,        phenylaminocarbonyl etc.) optionally substituted by C₁₋₄ alkyl        (e.g., methyl) optionally having halogen atom (e.g., fluorine)        (specific examples: phenylaminocarbonyl,        3-trifluoromethylphenylaminocarbonyl,        4-trifluoromethylphenylaminocarbonyl etc.), (2′) C₆₋₁₈        aryl-carbonyl (e.g., phenylcarbonyl etc.) optionally substituted        by C₁₋₄ alkyl (e.g., methyl) optionally having halogen atom        (e.g., fluorine) (specific examples: phenylcarbonyl,        3-trifluoromethylphenylcarbonyl etc.), and (3′) 5- or 6-membered        monocyclic aromatic heterocycle (e.g., pyrazolyl etc.)-carbonyl        containing, as ring-constituting atom, 1 to 3 heteroatoms        selected from oxygen atom, sulfur atom and nitrogen atom besides        carbon atoms, which is optionally substituted by C₁₋₄ alkyl        (e.g., methyl) and the like (specific examples:        1,3-dimethyl-1H-pyrazole-5-carbonyl etc.), wherein said fused        aromatic heterocycle further has 1 or 2 C₁₋₄ alkyl (e.g., methyl        etc.), and the like.

Particularly, C₆₋₁₄ aryl (e.g., phenyl etc.) substituted by aminooptionally substituted by (1) C₆₋₁₈ aryl-aminocarbonyl (e.g.,phenylaminocarbonyl etc.) optionally substituted by C₁₋₄ alkyl (e.g.,methyl) optionally having halogen atom (e.g., fluorine) (specificexamples: phenylaminocarbonyl, 3-trifluoromethylphenylaminocarbonyl,4-trifluoromethylphenylaminocarbonyl etc.), (2) C₆₋₁₈ aryl-carbonyl(e.g., phenylcarbonyl etc.) optionally substituted by C₁₋₄ alkyl (e.g.,methyl) optionally having halogen atom (e.g., fluorine) (specificexamples: phenylcarbonyl, 3-trifluoromethylphenylcarbonyl etc.), and (3)5- or 6-membered monocyclic aromatic heterocycle (e.g., pyrazolyletc.)-carbonyl containing, as ring-constituting atom, 1 to 3 heteroatomsselected from oxygen atom, sulfur atom and nitrogen atom besides carbonatoms, which is optionally substituted by C₁₋₄ alkyl (e.g., methyl) andthe like (specific examples: 1,3-dimethyl-1H-pyrazole-5-carbonyl etc.),wherein said C₆₋₁₄ aryl does not have further substituent, ispreferable.

As ring Yb, 3-aminophenyl, 4-aminophenyl,3-{[(ethylamino)carbonyl]amino}phenyl,4-{[(phenylamino)carbonyl]amino}phenyl,3-{[(phenylamino)carbonyl]amino}phenyl,3-({[3-(trifluoromethylphenyl)amino]carbonyl}amino)phenyl,3-({[4-(trifluoromethylphenyl)amino]carbonyl}amino)phenyl,3-[(tert-butylcarbonyl)amino]phenyl,3-[(cyclopropylcarbonyl)amino]phenyl,3-[(cyclohexylcarbonyl)amino]phenyl, 3-[(phenylcarbonyl)amino]phenyl,3-{[3-(trifluoromethylphenyl)carbonyl]amino}phenyl,3-{[3-(fluorophenyl)carbonyl]amino}phenyl,3-{[3-(chlorophenyl)carbonyl]amino}phenyl,3-{[3-(pyridyl)carbonyl]amino}phenyl,3-{[2-(furyl)carbonyl]amino}phenyl,3-{[3-(2,5-dimethylfuran)carbonyl]amino}phenyl,3-{[2-(3-methylthiophene)carbonyl]amino}phenyl,3-{[5-(4-methyl-1,2,3-thiadiazole)carbonyl]amino}phenyl,3-{[5-(isoxazole)carbonyl]amino}phenyl,3-{[5-(1,3-dimethyl-1H-pyrazole)carbonyl]amino}phenyl,3-{[5-(3-methylisoxazole)carbonyl]amino}phenyl,3-{[3-(5-methylisoxazole)carbonyl]amino}phenyl,3-({5-[1-methyl-3-(trifluoromethyl)-1H-pyrazole]carbonyl}amino)phenyl,5-methyl-2-(trifluoromethyl)-3-furancarbonylaminophenyl,3-{[5-(2,4-dimethyl-1,3-thiazole)carbonyl]amino}phenyl,3-{[4-(2,5-dimethyl-1,3-oxazole)carbonyl]amino}phenyl,3-{[5-(1-methyl-1H-pyrazole)carbonyl]amino}phenyl,3-{[3-(1,5-dimethyl-1H-pyrazole)carbonyl]amino}phenyl,3-{[4-(3,5-dimethylisoxazole)carbonyl]amino}phenyl,3-{[5-(1-methyl-1H-1,2,3-triazole)carbonyl]amino}phenyl,3-{[4-(1-methyl-1H-1,2,3-triazole)carbonyl]amino}phenyl,3-{[2-(1-methyl-1H-imidazole)carbonyl]amino}phenyl,3-{[5-(1-methyl-1H-imidazole)carbonyl]amino}phenyl,5-amino-2-methylphenyl, 3-amino-2-methylphenyl, 3-amino-4-methylphenyl,3-amino-4-chlorophenyl, 5-amino-2-chlorophenyl, 5-amino-2-methoxyphenyl,6-methyl-3-{[5-(1,3-dimethyl-1H-pyrazole)carbonyl]amino}phenyl,2-methyl-3-{[5-(1,3-dimethyl-1H-pyrazole)carbonyl]amino}phenyl,4-methyl-3-{[5-(1,3-dimethyl-1H-pyrazole)carbonyl]amino}phenyl,4-chloro-3-{[5-(1,3-dimethyl-1H-pyrazole)carbonyl]amino}phenyl,6-chloro-3-{[5-(1,3-dimethyl-1H-pyrazole)carbonyl]amino}phenyl,4-fluoro-3-{[5-(1,3-dimethyl-1H-pyrazole)carbonyl]amino}phenyl,6-methoxy-3-{[5-(1,3-dimethyl-1H-pyrazole)carbonyl]amino}phenyl,4-chloro-3-(cyclopropylcarbonylamino)phenyl, 3-amino-4-fluorophenyl andthe like can be specifically mentioned. Of these, 3-aminophenyl,4-aminophenyl, 4-{[(phenylamino)carbonyl]amino}phenyl,3-{[(phenylamino)carbonyl]amino}phenyl,3-({[3-(trifluoromethylphenyl)amino]carbonyl}amino)phenyl,3-({[4-(trifluoromethylphenyl)amino]carbonyl}amino)phenyl,3-{[5-(1,3-dimethyl-1H-pyrazole)carbonyl]amino}phenyl,4-fluoro-3-{[4-(1-ethyl-3-methyl-1H-pyrazole)carbonyl]amino}phenyl andthe like are preferable.

In the compound (III), as the substituent for R^(b) of NR defined by Xb,those similar to the substituent selected from the aforementionedSubstituent Group (1) can be mentioned.

As the substituent for R^(b), optionally substituted hydrocarbon groupand the like are preferable.

Xb is preferably —O—, —S— or —NH—, and particularly preferably —O—.

As the “substituent (except for optionally substituted amino)” forR^(1b), those similar to the group of the substituents of theaforementioned Substituent Group (1) except for the “optionallysubstituted amino” can be mentioned. Of these, optionally substitutedaminocarbonyl and the like are preferable.

Preferable R^(1b) are

(1) hydrogen atom,

(2) optionally substituted aminocarbonyl,

(3) optionally substituted alkyl,

(4) optionally esterified carboxy,

and the like.

Of these, more preferable R^(1b) are

(1) hydrogen atom,

(2) aminocarbonyl optionally substituted by optionally substitutedalkyl,

(3) alkyl optionally substituted by hydroxy,

(4) carboxy,

(5) C₁₋₆ alkoxy-carbonyl (e.g., ethoxycarbonyl),

and the like.

Hereinafter the preferable examples of the “substituent” for R^(1b) areexplained in detail.

As the “alkyl” of the “optionally substituted alkyl” of theabove-mentioned (2), C₁₋₈ alkyl and the like are preferable, C₁₋₄ alkyland the like are more preferable, and methyl and the like arespecifically preferable.

As the “alkyl” of the “alkyl optionally substituted hydroxy” of theabove-mentioned (3), C₁₋₈ alkyl and the like are preferable, C₁₋₄ alkyland the like are more preferable, and methyl and the like arespecifically preferable.

As R^(b), hydroxymethyl, —C(O)NH—CH₃, hydrogen atom, carboxy,ethoxycarbonyl and the like can be specifically mentioned.

In the compound (III), as the “substituent” for R^(2b), those similar tothe substituents of the aforementioned Substituent Group (1) can bementioned.

Of these, preferable R^(2b) is hydrogen atom.

In the compound (III), as the “substituent” for R^(3b), those similar tothe substituents of the aforementioned Substituent Group (1) can bementioned.

Of these, preferable R^(3b) is hydrogen atom.

In the compound (III), as the “substituent” for R^(4b), those similar tothe substituents of the aforementioned Substituent Group (1) can bementioned.

Of these, preferable R^(4b) is hydrogen atom.

As the preferable example of the compound (III), for example, thefollowing compound can be mentioned.

A compound wherein

ring Yb is C₆₋₁₄ aryl (e.g., phenyl etc.) substituted by aminooptionally substituted by (1) C₆₋₁₈ aryl-aminocarbonyl (e.g.,phenylaminocarbonyl etc.) optionally substituted by C₁₋₄ alkyl (e.g.,methyl) optionally having halogen atom (e.g., fluorine) (specificexamples: phenylaminocarbonyl, 3-trifluoromethylphenylaminocarbonyl,4-trifluoromethylphenylaminocarbonyl etc.), (2) C₆₋₁₈ aryl-carbonyl(e.g., phenylcarbonyl etc.) optionally substituted by C₁₋₄ alkyl (e.g.,methyl) optionally having halogen atom (e.g., fluorine) (specificexamples: phenylcarbonyl, 3-trifluoromethylphenylcarbonyl etc.), and (3)5- or 6-membered monocyclic aromatic heterocycle (e.g., pyrazolyletc.)-carbonyl containing, as ring-constituting atom, 1 to 3 heteroatomsselected from oxygen atom, sulfur atom and nitrogen atom besides carbonatoms, which is optionally substituted by C₁₋₄ alkyl (e.g., methyl) andthe like (specific examples: 1,3-dimethyl-1H-pyrazole-5-carbonyl etc.),wherein said C₆₋₁₄ aryl does not have further substituent;Xb is —O—, —S— or —NH— (preferably —O—);R^(1b) is(1) hydrogen atom,(2) —C(O)NH—CH₃, or(3) hydroxymethyl; andR^(2b), R^(3b) and R^(4b) are each hydrogen atom.

Specific examples of the compound (III) include Examples 61 to 63, 65,73, 124, 125, 139 to 146, 440, 442 and 445.

Examples of the salt of compounds (I)-(IV) include a metal salt, anammonium salt, a salt with organic base, a salt with inorganic acid, asalt with organic acid, a salt with basic or acidic amino acid and thelike. Preferable examples of the metal salt include alkali metal saltsuch as sodium salt, potassium salt and the like; alkaline earth metalsalt such as calcium salt, magnesium salt, barium salt and the like;aluminum salt and the like. Preferable examples of the salt with theorganic base include a salt with trimethylamine, triethylamine,pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine,triethanolamine, cyclohexylamine, dicyclohexylamine,N,N′-dibenzylethylenediamine and the like. Preferable examples of thesalt with the inorganic acid include a salt with hydrochloric acid,hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and thelike. Preferable examples of the salt with the organic acid include asalt with formic acid, acetic acid, trifluoroacetic acid, phthalic acid,fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid,succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid and the like. Preferable examples of the saltwith the basic amino acid include a salt with arginine, lysine,ornithine and the like. Preferable examples of the salt with the acidicamino acid include a salt with aspartic acid, glutamic acid and thelike.

Of these, pharmaceutically acceptable salt is preferable. For example,where the compound has an acidic functional group, inorganic salt suchas alkali metal salt (e.g., sodium salt, potassium salt etc.), alkalineearth metal salt (e.g., calcium salt, magnesium salt etc.) and the like,ammonium salt and the like can be mentioned. Alternatively, where thecompound has a basic functional group, for example, a salt withinorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid,sulfuric acid, phosphoric acid and the like, or a salt with organic acidsuch as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaricacid, maleic acid, citric acid, succinic acid, methanesulfonic acid,benzenesulfonic acid, p-toluenesulfonic acid and the like can bementioned.

Hereinafter, the production methods of compounds (I)-(IV) of the presentinvention are explained.

The compounds (I)-(IV) of the present invention can be obtained, forexample, according to the methods shown in the following Schemes or amethod analogous thereto and the like (while the production methods ofcompounds (II) and (III) are exemplarily shown below, compounds (I) and(IV) can also be obtained according to a method shown by a similarScheme or a method analogous thereto and the like).

Each compound in the following Schemes includes salts, and as suchsalts, for example, those similar to the salts of the compounds (I)-(IV)and the like can be used.

The compound obtained in each step can be used in the form of a reactionmixture or a crude product for the next reaction. In addition, thecompound can be isolated from a reaction mixture according to aconventional method, and can be easily purified by a separation meanssuch as recrystallization, distillation, chromatography and the like.

Schematic reaction formulas are shown in the following, wherein eachsymbol in the compounds is as defined above.

Moreover, the respective terms in the production methods mean thefollowing.

The “halogen atom” means fluorine, chlorine, bromine or iodine.

The “optionally substituted alkylsulfonyl” means C₁₋₆ alkylsulfonyl(e.g., methylsulfonyl, ethylsulfonyl etc.) optionally substituted bysubstituent(s) selected from halogen atom, optionally halogenated C₁₋₆alkyl (e.g., methyl, ethyl, trifluoromethyl) and nitro.

The “optionally substituted alkylsulfonyloxy” means C₁₋₆alkylsulfonyloxy (e.g., methylsulfonyloxy, ethylsulfonyloxy etc.)optionally substituted by substituent(s) selected from halogen atom,optionally halogenated C₁₋₆ alkyl (e.g., methyl, ethyl, trifluoromethyl)and nitro.

The “optionally substituted arylsulfonyloxy” means C₆₋₁₄ arylsulfonyloxy(e.g., phenylsulfonyloxy etc.) optionally substituted by substituent(s)selected from halogen atom, optionally halogenated C₁₋₆ alkyl (e.g.,methyl, ethyl, trifluoromethyl) and nitro.

The “optionally substituted aryloxy” means C₆₋₁₄ aryloxy (e.g.,phenyloxy etc.) optionally substituted by substituent(s) selected fromhalogen atom, optionally halogenated C₁₋₆ alkyl (e.g., methyl, ethyl,trifluoromethyl) and nitro.

The “optionally substituted alkoxy” means C₁₋₆ alkoxy (e.g., methoxy,ethoxy etc.) optionally substituted by substituent(s) selected fromhalogen atom, optionally halogenated C₁₋₆ alkyl (e.g., methyl, ethyl,trifluoromethyl) and nitro.

[Production Method 1]

wherein L¹ is a leaving group, M is a hydrogen atom or a metal atom, andother symbols are as defined above.

As the leaving group for L¹, for example, a halogen atom, optionallysubstituted alkylsulfonyl, optionally substituted alkylsulfonyloxy,optionally substituted arylsulfonyloxy and the like can be used.

M is mainly a hydrogen atom, but may be an alkali metal such as lithium,sodium, potassium, cesium and the like, or an alkaline earth metal suchas magnesium, calcium and the like.

Compound (II) can be produced by reacting compound (V-1) with compound(VI-1). Compound (VI-1) is used in 0.1 to 10 equivalents, preferably 0.3to 3 equivalents, relative to compound (V-1). A base may be added asnecessary. As the base, inorganic base or organic base and the like canbe used. Specifically, for example, sodium hydroxide, potassiumhydroxide, sodium carbonate, potassium carbonate, cesium carbonate,sodium bicarbonate, triethylamine, N-ethyldiisopropylamine,N-methylmorpholine, 1,8-diazabicyclo[5.4.0]undec-7-ene, pyridine,4-(dimethylamino)pyridine, N,N-dimethylaniline, sodium methoxide, sodiumethoxide, potassium tert-butoxide, sodium hydride, sodium amide, lithiumdiisopropylamide and the like can be mentioned. The base is used in 1 to30 equivalents, preferably 1 to 10 equivalents, relative to compound(V-1). This reaction is advantageously carried out using a solvent inertto the reaction. While the solvent is not particularly limited as longas the reaction proceeds, for example, alcohols such as methanol,ethanol, 2-propanol, 2-methyl-2-propanol and the like, ethers such asdiethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and thelike, hydrocarbons such as benzene, toluene, cyclohexane, hexane and thelike, esters such as ethyl acetate and the like, ketones such asacetone, methyl ethyl ketone and the like, amides such asN,N-dimethylformamide, N,N-dimethylacetamide, 1-methyl-2-pyrrolidone andthe like, halogenated hydrocarbons such as dichloromethane, chloroform,carbon tetrachloride, 1,2-dichloroethane and the like, nitriles such asacetonitrile and the like, sulfoxides such as dimethylsulfoxide and thelike, pyridine, water and the like can be used alone or in mixture.While the reaction time varies depending on the kind of reagent andsolvent to be used, it is generally 1 min to 200 hr, preferably 10 minto 100 hr. While the reaction temperature varies depending on the kindof reagent and solvent to be used, it is generally −100 to 250° C.,preferably −78 to 200° C. The reaction can be carried out using amicrowave synthesizer.

A compound within the scope of the present invention can also beproduced by applying a means known per se to the obtained compound (II)of the present invention for introduction of substituents and conversionof functional groups. For conversion of substituents, a knownconventional method can be used. For example, conversion to carboxy byhydrolysis of ester, conversion to carbamoyl by amidation of carboxy,conversion to hydroxymethyl by reduction of carboxy, conversion toalcohol compound by reduction or alkylation of carbonyl, reductiveamination of carbonyl, oximation of carbonyl, acylation, ureation,sulfonylation or alkylation of amino, substitution and amination ofactive halogen by amine, amination of nitro by reduction, alkylation ofhydroxy, substitution and amination of hydroxy and the like can bementioned. When a reactive substituent that causes non-objectivereaction is present during the introduction of substituents andconversion of functional groups, a protecting group is introduced inadvance as necessary into the reactive substituent by a means known perse, and the protecting group is removed by a means known per se afterthe objective reaction, whereby the compound within the scope of thepresent invention can also be produced.

Compound (VI-1) may be commercially available, or can be producedaccording to a method known per se, for example, the methods describedin “Advanced Organic Chemistry, 4th Ed.” (Jerry March), “ComprehensiveOrganic Transformations, 2nd Ed.” (Richard C. Larock) and the like or amethod analogous thereto.

[Production Method 2]

Compound (II) wherein Ya is substituted by optionally substituted amide,which is further optionally substituted, can also be produced forexample, according to a method shown in Scheme 2. Compounds (II-1),(II-2) and (II-3) are encompassed in compound (II).

wherein L² is a leaving group, Ya′ is a cyclic group of Ya, R¹⁰ is agroup shown by the moiety of acyl except for carbonyl moiety, which acylis exemplified as the substituent of the “optionally substituted amino”which is one of the substituents of the “optionally substituted cyclicgroup” for ring Y of compound (I), and other symbols are as definedabove.

As the leaving group for L², for example, halogen atom, optionallysubstituted aryloxy, optionally substituted alkoxy, 1-imidazolyl and thelike can be used.

In Method A, compound (II-2) is produced by reacting compound (V-1) andcompound (VI-2) in the presence of a base, and reducing the nitro ofcompound (II-1). Compound (VI-2) is used in 0.1 to 10 equivalents,preferably 0.3 to 3 equivalents, relative to compound (V-1). As thebase, those similar to the base exemplified in Scheme 1 can be used. Thebase is used in 1 to 30 equivalents, preferably 1 to 10 equivalents,relative to compound (V-1). This reaction is advantageously carried outusing a solvent inert to the reaction. As the solvent, those similar tothe solvents exemplified in Scheme 1 can be used. The reaction time isgenerally 1 min to 200 hr, preferably 10 min to 100 hr. The reactiontemperature is generally −100° C. to 250° C., preferably −78° C. to 200°C. Compound (VI-2) may be commercially available, or can be producedaccording to a method known per se, for example, the methods describedin “Advanced Organic Chemistry, 4th Ed.” (Jerry March), “ComprehensiveOrganic Transformations, 2nd Ed.” (Richard C. Larock) and the like or amethod analogous thereto. The obtained compound (II-1) can be used as areaction mixture or as a crude product in the next reaction. It can beisolated from a reaction mixture according to a conventional method. Thereduction of nitro can be carried out according to a method known perse, for example, the methods described in the fourth series ofexperimental chemistry, vol. 20, 279-280 and the like, or a methodanalogous thereto.

In Method B, compound (II-2) is produced by reacting compound (V-1) withcompound (VI-3) in the presence of a base. Compound (VI-3) is used in0.1 to 10 equivalents, preferably 0.3 to 3 equivalents, relative tocompound (V-1). As the base, those similar to the base exemplified inScheme 1 can be used. The base is used in 1 to 30 equivalents,preferably 1 to 10 equivalents, relative to compound (V-1). Thisreaction is advantageously carried out using a solvent inert to thereaction. As the solvent, those similar to the solvents exemplified inScheme 1 can be used. The reaction time is generally 1 min to 200 hr,preferably 10 min to 100 hr. The reaction temperature is generally −100°C. to 250° C., preferably −78° C. to 200° C. Compound (VI-3) may becommercially available, or can be produced according to a method knownper se, for example, the methods described in “Advanced OrganicChemistry, 4th Ed.” (Jerry March), “Comprehensive OrganicTransformations, 2nd Ed.” (Richard C. Larock) and the like or a methodanalogous thereto.

In Method C, compound (II-3) is produced by reacting compound (II-2)with a compound represented by the formula R¹⁰C(O)L². The compoundrepresented by the formula R¹⁰C(O)L² is used in 0.1 to 10 equivalents,preferably 0.3 to 3 equivalents, relative to compound (II-2). A base maybe used in 0.01 to 10 equivalents, preferably 0.03 to 5 equivalents,relative to compound (II-2). As the base, those similar to the baseexemplified in Scheme 1 can be used. This reaction is advantageouslycarried out using a solvent inert to the reaction. As the solvent, thosesimilar to the solvents exemplified in Scheme 1 can be used. Thereaction time is generally 1 min to 200 hr, preferably 10 min to 100 hr.The reaction temperature is generally −100° C. to 250° C., preferably−78° C. to 200° C. The compound represented by the formula R¹⁰C(O)L² maybe commercially available, or can be produced according to a methodknown per se, for example, the methods described in “Advanced OrganicChemistry, 4th Ed.” (Jerry March), “Comprehensive OrganicTransformations, 2nd Ed.” (Richard C. Larock) and the like or a methodanalogous thereto.

In Method D, (II-3) is produced by reacting compound (II-2) withcarboxylic acid (R¹⁰CO₂H) in the presence of a condensing agent. WhenCompound (II-2) is reacted with carboxylic acid (R¹⁰CO₂H) in thepresence of a condensing agent, carboxylic acid (R¹⁰CO₂H) is used in 0.1to 10 equivalents, preferably 0.3 to 3 equivalents, relative to compound(II-2). As the condensing agent, for example,1-ethyl-1-(3-dimethylaminopropyl)carbodiimide hydrochloride,1,3-dicyclohexylcarbodiimide, diethyl cyanophosphate, diphenylphosphorylazide, 1,1′-carbonyldiimidazole,benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate,O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate,O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate and the like can be used. The condensing agent isused in 1 to 10 equivalents, preferably 1 to 5 equivalents, relative tocompound (II-2). Where necessary, a suitable condensation promoter(e.g., 1-hydroxybenzotriazole, N-hydroxysuccinimide etc.) can be used.The condensation promoter is used in 0.1 to 10 equivalents, preferably0.3 to 3 equivalents, relative to compound (II-2). This reaction mayproceed more smoothly when a base is added. As the base, those similarto the bases exemplified in Scheme 1 can be used. The base is used in0.01 to 10 equivalents, preferably 0.03 to 5 equivalents, relative tocompound (II-2). This reaction is advantageously carried out using asolvent inert to the reaction. As the solvent, those similar to thesolvents exemplified in Scheme 1 can be used. The reaction time isgenerally 1 min to 200 hr, preferably 10 min to 100 hr. The reactiontemperature is generally −100° C. to 250° C., preferably −78° C. to 200°C. Carboxylic acid (R¹⁰CO₂H) may be commercially available, or can beproduced according to a method known per se, for example, the methodsdescribed in “Advanced Organic Chemistry, 4th Ed.” (Jerry March),“Comprehensive Organic Transformations, 2nd Ed.” (Richard C. Larock) andthe like or a method analogous thereto.

[Production Method 3]

In compound (II), when Ya is substituted by optionally substitutedureido, and optionally further substituted, for example, the compoundcan also be produced by the method shown in Scheme 3. Compounds (II-2),(II-4) and (II-5) are encompassed in compound (II).

wherein L³ is a leaving group, —NR¹¹R¹² is a group shown by the moietyof optionally substituted aminocarbonyl except for carbonyl moiety,which optionally substituted aminocarbonyl is exemplified as thesubstituent of the “optionally substituted amino” which is one of thesubstituents of the “optionally substituted cyclic group” for ring Y ofcompound (I), and other symbols are as defined above.

As the leaving group for L³, for example, a halogen atom, optionallysubstituted aryloxy, optionally substituted alkoxy, 1-imidazolyl and thelike can be used.

In Method E, compound (II-5) is produced by reacting compound (II-2)with the isocyanate derivative (R¹¹NCO). Isocyanate derivative (R¹¹NCO)is used in 0.1 to 10 equivalents, preferably 0.3 to 3 equivalents,relative to compound (II-2). A base may be used in 0.01 to 10equivalents, preferably 0.01 to 3 equivalents. As the base, thosesimilar to the base exemplified in Scheme 1 can be used. This reactionis advantageously carried out using a solvent inert to the reaction. Asthe solvent, those similar to the solvents exemplified in Scheme 1 canbe used. The reaction time is generally 1 min to 200 hr, preferably 10min to 100 hr. The reaction temperature is generally −100° C. to 250°C., preferably −78° C. to 200° C. Isocyanate derivative (R¹¹NCO) may becommercially available, or can be produced according to a method knownper se, for example, the methods described in “Advanced OrganicChemistry, 4th Ed.” (Jerry March), “Comprehensive OrganicTransformations, 2nd Ed.” (Richard C. Larock) and the like or a methodanalogous thereto.

In Method F-1, compound (II-5) is produced by first reacting compound(II-2) with a compound represented by the formula L²C(O)L³ to givecompound (II-4), and then reacting compound (II-4) with amine derivative(R¹¹R¹²NH). The compound represented by the formula L²C(O)L³ is used in0.1 to 10 equivalents, preferably 0.3 to 3 equivalents, relative tocompound (II-2). A base may be used in 0.1 to 10 equivalents, preferably0.3 to 3 equivalents. As the base, those similar to the base exemplifiedin Scheme 1 can be used. This reaction is advantageously carried outusing a solvent inert to the reaction. As the solvent, those similar tothe solvents exemplified in Scheme 1 can be used. The reaction time isgenerally 1 min to 200 hr, preferably 10 min to 100 hr. The reactiontemperature is generally −100° C. to 250° C., preferably −78° C. to 200°C. The compound represented by the formula L²C(O)L³ may be commerciallyavailable, or can be produced by a method known per se. The obtainedcompound (II-4) can be used in the form of a reaction mixture or a crudeproduct for the next reaction. It can also be used for the next reactionafter isolation and purification from a reaction mixture according to aconventional method. The amine derivative (R¹¹R¹²NH) is used in 0.1 to10 equivalents, preferably 0.3 to 3 equivalents, relative to compound(II-4). In addition, a base may be used in 0.1 to 10 equivalents,preferably 0.3 to 3 equivalents. As the base, those similar to the baseexemplified in Scheme 1 can be used. This reaction is advantageouslycarried out using a solvent inert to the reaction. As the solvent, thosesimilar to the solvents exemplified in Scheme 1 can be used. Thereaction time is generally 1 min to 200 hr, preferably 10 min to 100 hr.The reaction temperature is generally −100° C. to 250° C., preferably−78° C. to 200° C. The amine derivative (R¹¹R¹²NH) may be commerciallyavailable, or can be produced according to a method known per se, forexample, the methods described in “Advanced Organic Chemistry, 4th Ed.”(Jerry March), “Comprehensive Organic Transformations, 2nd Ed.” (RichardC. Larock) and the like or a method analogous thereto.

In Method F-2, compound (II-5) is produced by first reacting a compoundrepresented by the formula R¹¹R¹²NH with a compound represented by theformula L²C(O)L³, successively compound (II-2) to give compound (II-5).The compound represented by the formula L²C(O)L³ is used in 0.1 to 10equivalents, preferably 0.3 to 3 equivalents, relative to aminederivative (R¹¹R¹²NH). A base may be used in 0.1 to 10 equivalents,preferably 0.3 to 3 equivalents. As the base, those similar to the baseexemplified in Scheme 1 can be used. This reaction is advantageouslycarried out using a solvent inert to the reaction. As the solvent, thosesimilar to the solvents exemplified in Scheme 1 can be used. Thereaction time is generally 1 min to 200 hr, preferably 10 min to 100 hr.The reaction temperature is generally −100° C. to 250° C., preferably−78° C. to 200° C. The amine derivative (R¹¹R¹²NH) and the compoundrepresented by the formula L²C(O)L³ may be commercially available, orcan be produced by a method known per se for example, the methodsdescribed in “Advanced Organic Chemistry, 4th Ed.” (Jerry March),“Comprehensive Organic Transformations, 2nd Ed.” (Richard C. Larock) andthe like or a method analogous thereto. The obtained compoundrepresented by the formula R¹¹R¹²NC(O)L³ can be used in the form of areaction mixture or a crude product for the next reaction. It can alsobe used for the next reaction after isolation and purification from areaction mixture according to a conventional method. The compound (II-2)is used in 0.1 to 10 equivalents, preferably 0.3 to 3 equivalents,relative to the compound represented by the formula R¹¹R¹²NC(O)L³. Inaddition, a base may be used in 0.1 to 10 equivalents, preferably 0.3 to3 equivalents. As the base, those similar to the base exemplified inScheme 1 can be used. This reaction is advantageously carried out usinga solvent inert to the reaction. As the solvent, those similar to thesolvents exemplified in Scheme 1 can be used. The reaction time isgenerally 1 min to 200 hr, preferably 10 min to 100 hr. The reactiontemperature is generally −100° C. to 250° C., preferably −78° C. to 200°C.

[Production Method 4]

In compound (II), when Ya is substituted by optionally substitutedsulfonamide, and optionally further substituted, for example, thecompound can also be produced by the method shown in Scheme 4. Compound(II-6) is encompassed in compound (II).

wherein R¹³ is a group shown by the moiety of acyl except for carbonylmoiety, which acyl is exemplified as the substituent of the “optionallysubstituted amino” which is one of the substituents of the “optionallysubstituted cyclic group” for ring Y of compound (I), and other symbolsare as defined above.

Compound (II-6) can be produced by reacting compound (II-2) with areactive derivative of sulfonic acid (R¹³SO₂L²). The reactive derivativeof sulfonic acid (R¹³SO₂L²) is used in 0.1 to 10 equivalents, preferably0.3 to 3 equivalents, relative to compound (II-2). In the presentmethod, the reaction is generally carried out in the presence of a base,though it is not always essential. As the base, those similar to thebase exemplified in Scheme 1 can be used. A base may be used in 0.01 to10 equivalents, preferably 0.03 to 5 equivalents, relative to compound(II-2). This reaction is advantageously carried out using a solventinert to the reaction. As the solvent, those similar to the solventsexemplified in Scheme 1 can be used. The reaction time is generally 1min to 200 hr, preferably 10 min to 100 hr. The reaction temperature isgenerally −100° C. to 250° C., preferably −78° C. to 200° C. Thereactive derivative of sulfonic acid (R¹³SO₂L²) may be commerciallyavailable, or can be produced according to a method known per se, forexample, the methods described in “Advanced Organic Chemistry, 4th Ed.”(Jerry March), “Comprehensive Organic Transformations, 2nd Ed.” (RichardC. Larock) and the like or a method analogous thereto.

[Production Method 5]

Compound (V-1) shown in Schemes 1 and 2 can be obtained, for example, bythe method shown in the following Scheme or a method analogous theretoand the like. Compounds (V-2), (V-3) and (V-4) are encompassed incompound (V-1).

wherein L⁴ is a leaving group, R¹⁴ is an optionally substitutedhydrocarbon group, R¹⁵ is an optionally substituted hydrocarbon group oroptionally substituted cyclic group, and other symbols are as definedabove.

As the leaving group for L⁴, chlorine, bromine, iodine and the like canbe used.

Examples of the optionally substituted hydrocarbon group for R¹⁴ includemethyl, ethyl, propyl, isopropyl, tert-butyl and the like.

Examples of the optionally substituted hydrocarbon group, optionallysubstituted cyclic group for R¹⁵ include a group shown by the moiety ofacyl except for carbonyl group, which acyl is exemplified as thesubstituent of the “optionally substituted amino” for R^(1a) of compound(II) and the like.

In Method G, compound (V-2) is produced by reacting compound (VII-1)with an acetylcarbamic acid derivative (L⁴CHR^(2a)C(O)NHC(O)OR¹⁴). Theacetylcarbamic acid derivative is used in 0.1 to 10 equivalents,preferably 0.3 to 5 equivalents, relative to compound (VII-1). A basemay be used in 0.1 to 10 equivalents, preferably 0.3 to 5 equivalents,relative to compound (VII-1). As the base, inorganic base or organicbase and the like can be used, specifically, for example, sodiumcarbonate, potassium carbonate, cesium carbonate, sodium bicarbonate,disodium hydrogenphosphate, dipotassium hydrogenphosphate, calciumhydrogenphosphate, triethylamine, N-ethyldiisopropylamine,N-methylmorpholine, 1,8-diazabicyclo[5.4.0]undec-7-ene, pyridine,4-(dimethylamino)pyridine, N,N-dimethylaniline and the like can be used.This reaction is advantageously carried out using a solvent inert to thereaction. As the solvent, those similar to the solvents exemplified inScheme 1 can be used. The reaction time is generally 1 min to 200 hr,preferably 10 min to 100 hr. The reaction temperature is generally −100°C. to 250° C., preferably −78° C. to 200° C. The acetylcarbamic acidderivative (L⁴CHR^(2a)C(O)NHC(O)OR¹⁴) may be commercially available, orcan be produced according to a method known per se, for example, themethods described in “Journal of Organic Chemistry, 50, 2480-2499(1985)” and the like or a method analogous thereto.

In Method H, compound (V-3) is produced by treating compound (V-2) witha base or acid. As the base, for example, sodium hydroxide, potassiumhydroxide, cesium hydroxide, barium hydroxide and the like can bementioned. A base is used in 0.01 to 10 equivalents, preferably 0.03 to5 equivalents, relative to compound (V-2). As the acid, for example,hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid,trifluoroacetic acid and the like can be used. An acid is used in 0.1 to20 equivalents, preferably 0.3 to 10 equivalents, relative to compound(V-2). This reaction is advantageously carried out using a solvent inertto the reaction. As the solvent, those similar to the solventsexemplified in Scheme 1 can be used.

In Method I, compound (V-4) is produced by reacting compound (V-3) witha compound represented by the formula R¹⁵C(O)L². The compoundrepresented by the formula R¹⁵C(O)L² is used in 0.1 to 10 equivalents,preferably 0.3 to 3 equivalents, relative to compound (V-3). As thebase, those similar to the base exemplified in Scheme 1 can be used. Abase may be used in 0.01 to 10 equivalents, preferably 0.03 to 5equivalents, relative to compound (V-3). This reaction is advantageouslycarried out using a solvent inert to the reaction. As the solvent, thosesimilar to the solvents exemplified in Scheme 1 can be used. Thereaction time is generally 1 min to 200 hr, preferably 10 min to 100 hr.The reaction temperature is generally −100° C. to 250° C., preferably−78° C. to 200° C. The compound represented by the formula R¹⁵C(O)L² maybe commercially available, or can be produced according to a methodknown per se, for example, the methods described in “Advanced OrganicChemistry, 4th Ed.” (Jerry March), “Comprehensive OrganicTransformations, 2nd Ed.” (Richard C. Larock) and the like or a methodanalogous thereto.

In Method J, (V-4) is produced by reacting compound (V-3) withcarboxylic acid (R¹⁵CO₂H) in the presence of a condensing agent. Whencompound (V-3) is reacted with carboxylic acid (R¹⁵CO₂H) in the presenceof a condensing agent, carboxylic acid (R¹⁵CO₂H) is used in 0.1 to 10equivalents, preferably 0.3 to 3 equivalents, relative to compound(V-3). As the condensing agent, for example,1-ethyl-1-(3-dimethylaminopropyl)carbodiimide hydrochloride,1,3-dicyclohexylcarbodiimide, diethyl cyanophosphate, diphenylphosphorylazide, 1,1′-carbonyldiimidazole,benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate,O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate,O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate and the like can be used. These condensing agentsare used in 1 to 10 equivalents, preferably 1 to 5 equivalents, relativeto compound (V-3). Where necessary, a suitable condensation promoter(e.g., 1-hydroxybenzotriazole, N-hydroxysuccinimide etc.) can be used.These condensation promoters are used in 0.1 to 10 equivalents,preferably 0.3 to 3 equivalents, relative to compound (V-3). Thisreaction may proceed more smoothly when a base is added. As the base,those similar to the base exemplified in Scheme 1 can be used. Thesebases are used in 0.01 to 10 equivalents, preferably 0.03 to 5equivalents, relative to compound (V-3). This reaction is advantageouslycarried out using a solvent inert to the reaction. As the solvent, thosesimilar to the solvents exemplified in Scheme 1 can be used. Thereaction time is generally 1 min to 200 hr, preferably 10 min to 100 hr.The reaction temperature is generally −100° C. to 250° C., preferably−78° C. to 200° C. Carboxylic acid (R¹⁵CO₂H) may be commerciallyavailable, or can be produced according to a method known per se, forexample, the methods described in “Advanced Organic Chemistry, 4th Ed.”(Jerry March), “Comprehensive Organic Transformations, 2nd Ed.” (RichardC. Larock) and the like or a method analogous thereto.

[Production Method 6]

wherein each symbol is as defined above.

Compound (III) can be produced by reacting compound (V-5) with compound(VI-4). Compound (VI-4) is used in 0.1 to 10 equivalents, preferably 0.3to 3 equivalents, relative to Compound (V-5). Where necessary, a basemay be added. As the base, those similar to the base exemplified inScheme 1 can be used. These bases are used in 1 to 30 equivalents,preferably 1 to 10 equivalents, relative to compound (V-5). Thisreaction is advantageously carried out using a solvent inert to thereaction. As the solvent, those similar to the solvents exemplified inScheme 1 can be used. The reaction time varies depending on the kind ofreagent and solvent to be used, and is generally 1 min to 200 hr,preferably 10 min to 100 hr. While the reaction temperature variesdepending on the kind of reagent and solvent to be used, generally −100°C. to 250° C., preferably −78° C. to 200° C. The reaction may be carriedout using a microwave synthesizer.

A compound within the scope of the present invention can also beproduced by applying a means known per se to the obtained compound (III)of the present invention for introduction of substituents and conversionof functional groups. For conversion of substituents, a knownconventional method can be used. For example, conversion to carboxy byhydrolysis of ester, conversion to carbamoyl by amidation of carboxy,conversion to hydroxymethyl by reduction of carboxy, conversion toalcohol compound by reduction or alkylation of carbonyl, reductiveamination of carbonyl, oximation of carbonyl, acylation, ureation,sulfonylation or alkylation of amino, substitution and amination ofactive halogen by amine, alkylation of hydroxy, substitution andamination of hydroxy and the like can be mentioned. When a reactivesubstituent that causes non-objective reaction is present during theintroduction of substituents and conversion of functional groups, aprotecting group is introduced in advance as necessary into the reactivesubstituent by a means known per se, and the protecting group is removedby a means known per se after the objective reaction, whereby thecompound within the scope of the present invention can also be produced.

Compound (VI-4) may be commercially available, or can be producedaccording to a method known per se, for example, the methods describedin “Advanced Organic Chemistry, 4th Ed.” (Jerry March), “ComprehensiveOrganic Transformations, 2nd Ed.” (Richard C. Larock) and the like or amethod analogous thereto.

[Production method 7]

In compound (III), when the substituent of optionally substituted aminofor Yb is acyl, for example, the compound can also be produced by themethod shown in Scheme 7. Compounds (III-1), (III-2) and (III-3) areencompassed in compound (III).

wherein Yb′ is a cyclic group of Yb, and other symbols are as definedabove.

In Method K, compound (III-2) is produced by first reacting compound(V-5) with compound (VI-5) in the presence of a base to give compound(III-1), and then reducing nitro of compound (III-1). Compound (VI-5) isused in 0.1 to 10 equivalents, preferably 0.3 to 3 equivalents, relativeto compound (V-5). As the base, those similar to the base exemplified inScheme 1 can be used. A base is used in 1 to 30 equivalents, preferably1 to 10 equivalents, relative to compound (V-5). This reaction isadvantageously carried out using a solvent inert to the reaction. As thesolvent, those similar to the solvents exemplified in Scheme 1 can beused. The reaction time is generally 1 min to 200 hr, preferably 10 minto 100 hr. The reaction temperature is generally −100° C. to 250° C.,preferably −78° C. to 200° C. Compound (VI-5) may be commerciallyavailable, or can be produced according to a method known per se, forexample, the method described in “Advanced Organic Chemistry, 4th Ed.”(Jerry March), “Comprehensive Organic Transformations, 2nd Ed.” (RichardC. Larock) and the like, or a method analogous thereto. The obtainedcompound (III-1) can be used in the form of a reaction mixture or acrude product for the next reaction. Alternatively, it may be used forthe next reaction after isolation and purification from the reactionmixture according to a conventional method. The reduction of nitro canbe carried out by a method known per se, for example, the methoddescribed in the fourth series of experimental chemistry, vol. 20,279-280 and the like, or a method analogous thereto.

In Method L, compound (III-2) is produced by reacting compound (V-5)with compound (VI-6) in the presence of a base. Compound (VI-6) is usedin 0.1 to 10 equivalents, preferably 0.3 to 3 equivalents, relative tocompound (V-5). As the base, those similar to the base exemplified inScheme 1 can be used. A base is used in 1 to 5 equivalents, preferably 1to 2 equivalents, relative to compound (V-5). This reaction isadvantageously carried out using a solvent inert to the reaction. As thesolvent, those similar to the solvents exemplified in Scheme 1 can beused. The reaction time is generally 1 min to 200 hr, preferably 10 minto 100 hr. The reaction temperature is generally −100° C. to 250° C.,preferably −78° C. to 200° C. Compound (VI-6) may be commerciallyavailable, or can be produced according to a method known per se, forexample, the method described in “Advanced Organic Chemistry, 4th Ed.”(Jerry March), “Comprehensive Organic Transformations, 2nd Ed.” (RichardC. Larock) and the like, or a method analogous thereto.

In Method M, compound (III-3) is produced by reacting compound (III-2)with a compound represented by the formula R¹⁰C(O)L². The compoundrepresented by the formula R¹⁰C(O)L² is used in 0.1 to 10 equivalents,preferably 0.3 to 3 equivalents, relative to compound (III-2). A basemay be used in 0.01 to 10 equivalents, preferably 0.03 to 5 equivalents,relative to compound (III-2). As the base, those similar to the baseexemplified in Scheme 1 can be used. This reaction is advantageouslycarried out using a solvent inert to the reaction. As the solvent, thosesimilar to the solvents exemplified in Scheme 1 can be used. Thereaction time is generally 1 min to 200 hr, preferably 10 min to 100 hr.The reaction temperature is generally −100° C. to 250° C., preferably−78° C. to 200° C. The compound represented by the formula R¹⁰C(O)L² maybe commercially available, or can be produced according to a methodknown per se, for example, the methods described in “Advanced OrganicChemistry, 4th Ed.” (Jerry March), “Comprehensive OrganicTransformations, 2nd Ed.” (Richard C. Larock) and the like or a methodanalogous thereto.

In Method N, compound (III-3) is produced by reacting compound (III-2)with carboxylic acid (R¹⁰CO₂H) in the presence of a condensing agent.When Compound (III-2) is reacted with carboxylic acid (R¹⁰CO₂H) in thepresence of a condensing agent, carboxylic acid (R¹⁰CO₂H) is used in 0.1to 10 equivalents, preferably 0.3 to 3 equivalents, relative to compound(III-2). As the condensing agent, for example,1-ethyl-1-(3-dimethylaminopropyl)carbodiimide hydrochloride,1,3-dicyclohexylcarbodiimide, diethyl cyanophosphate, diphenylphosphorylazide, 1,1′-carbonyldiimidazole,benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate,O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate,O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate and the like can be used. These condensing agentsare used in 1 to 10 equivalents, preferably 1 to 5 equivalents, relativeto compound (III-2). Where necessary, a suitable condensation promoter(e.g., 1-hydroxybenzotriazole, N-hydroxysuccinimide etc.) can be used.These condensation promoters are used in 0.1 to 10 equivalents,preferably 0.3 to 3 equivalents, relative to compound (III-2). Thisreaction may proceed more smoothly when a base is added. As the base,those similar to the base exemplified in Scheme 1 can be used. A base isused in 0.01 to 10 equivalents, preferably 0.03 to 5 equivalents,relative to compound (III-2). This reaction is advantageously carriedout using a solvent inert to the reaction. As the solvent, those similarto the solvents exemplified in Scheme 1 can be used. The reaction timeis generally 1 min to 200 hr, preferably 10 min to 100 hr. The reactiontemperature is generally −100° C. to 250° C., preferably −78° C. to 200°C. Carboxylic acid (R¹⁰CO₂H) may be commercially available, or can beproduced according to a method known per se, for example, the methodsdescribed in “Advanced Organic Chemistry, 4th Ed.” (Jerry March),“Comprehensive Organic Transformations, 2nd Ed.” (Richard C. Larock) andthe like or a method analogous thereto.

[Production Method 8]

Compound (III) wherein Yb is substituted by optionally substitutedureido, and optionally further substituted can also be produced, forexample, by the method shown in Scheme 8. Compounds (III-2), (III-4) and(III-5) are encompassed in compound (III).

wherein each symbol is as defined above.

In Method O, compound (III-5) is produced by reacting compound (III-2)with an isocyanate derivative (R¹¹NCO). The isocyanate derivative(R¹¹NCO) is used in 0.1 to 10 equivalents, preferably 0.3 to 3equivalents, relative to compound (III-2). In addition, a base may beused in 0.01 to 10 equivalents, preferably 0.01 to 3 equivalents. As thebase, those similar to the base exemplified in Scheme 1 can be used.This reaction is advantageously carried out using a solvent inert to thereaction. As the solvent, those similar to the solvents exemplified inScheme 1 can be used. The reaction time is generally 1 min to 200 hr,preferably 10 min to 100 hr. The reaction temperature is generally −100°C. to 250° C., preferably −78° C. to 200° C. An isocyanate derivative(R¹¹NCO) may be commercially available, or can be produced according toa method known per se, for example, the methods described in “AdvancedOrganic Chemistry, 4th Ed.” (Jerry March), “Comprehensive OrganicTransformations, 2nd Ed.” (Richard C. Larock) and the like or a methodanalogous thereto.

In Method P-1, compound (III-5) is produced by first reacting compound(III-2) with a compound represented by the formula L²C(O)L³ to givecompound (III-4), and then reacting compound (III-4) with an aminederivative (R¹¹R¹²NH). The compound represented by the formula L²C(O)L³is used in 0.1 to 10 equivalents, preferably 0.3 to 3 equivalents,relative to compound (III-2). A base may be used in 0.1 to 10equivalents, preferably 0.3 to 3 equivalents. As the base, those similarto the base exemplified in Scheme 1 can be used. This reaction isadvantageously carried out using a solvent inert to the reaction. As thesolvent, those similar to the solvents exemplified in Scheme 1 can beused. The reaction time is generally 1 min to 200 hr, preferably 10 minto 100 hr. The reaction temperature is generally −100° C. to 250° C.,preferably −78° C. to 200° C. The compound represented by the formulaL²C(O)L³ may be commercially available, or can be produced by a methodknown per se. The obtained compound (III-4) can be used in the form of areaction mixture or a crude product for the next reaction. It may beused for the next reaction after isolation and purification from thereaction mixture according to a conventional method. An amine derivative(R¹¹R¹²NH) is used in 0.1 to 10 equivalents, preferably 0.3 to 3equivalents, relative to compound (III-4). A base may be used in 0.1 to10 equivalents, preferably 0.3 to 3 equivalents. As the base, thosesimilar to the base exemplified in Scheme 1 can be used. This reactionis advantageously carried out using a solvent inert to the reaction. Asthe solvent, those similar to the solvents exemplified in Scheme 1 canbe used. The reaction time is generally 1 min to 200 hr, preferably 10min to 100 hr. The reaction temperature is generally −100° C. to 250°C., preferably −78° C. to 200° C. The amine derivative (R¹¹R¹²NH) may becommercially available, or can be produced according to a method knownper se, for example, the methods described in “Advanced OrganicChemistry, 4th Ed.” (Jerry March), “Comprehensive OrganicTransformations, 2nd Ed.” (Richard C. Larock) and the like or a methodanalogous thereto.

In Method P-2, compound (III-5) is produced by reacting amine derivative(R¹¹R¹²NH) with a compound represented by the formula L²C(O)L³successively with compound (III-2). The compound represented by theformula L²C(O)L³ is used in 0.1 to 10 equivalents, preferably 0.3 to 3equivalents, relative to the amine derivative (R¹¹R¹²NH). A base may beused in 0.1 to 10 equivalents, preferably 0.3 to 3 equivalents. As thebase, those similar to the base exemplified in Scheme 1 can be used.This reaction is advantageously carried out using a solvent inert to thereaction. As the solvent, those similar to the solvents exemplified inScheme 1 can be used. The reaction time is generally 1 min to 200 hr,preferably 10 min to 100 hr. The reaction temperature is generally −100°C. to 250° C., preferably −78° C. to 200° C. The amine derivative(R¹¹R¹²NH) and the compound represented by the formula L²C(O)L³ may becommercially available, or can be produced by a method known per se, forexample, the methods described in “Advanced Organic Chemistry, 4th Ed.”(Jerry March), “Comprehensive Organic Transformations, 2nd Ed.” (RichardC. Larock) and the like or a method analogous thereto. The obtainedcompound represented by the formula R¹¹R¹²NC(O)L³ can be used in theform of a reaction mixture or a crude product for the next reaction. Itmay be used for the next reaction after isolation and purification fromthe reaction mixture according to a conventional method. The compound(III-2) is used in 0.1 to 10 equivalents, preferably 0.3 to 3equivalents, relative to the compound represented by the formulaR¹¹R¹²NC(O)L³. A base may be used in 0.1 to 10 equivalents, preferably0.3 to 3 equivalents. As the base, those similar to the base exemplifiedin Scheme 1 can be used. This reaction is advantageously carried outusing a solvent inert to the reaction. As the solvent, those similar tothe solvents exemplified in Scheme 1 can be used. The reaction time isgenerally 1 min to 200 hr, preferably 10 min to 100 hr. The reactiontemperature is generally −100° C. to 250° C., preferably −78° C. to 200°C.

[Production Method 9]

Compound (III) wherein the substituent of the optionally substitutedamino for Yb is sulfonyl can also be produced, for example, by themethod shown in Scheme 9. Compound (III-6) is encompassed in compound(III).

wherein each symbol is as defined above.

Compound (III-6) can be produced by reacting compound (III-2) with areactive derivative of sulfonic acid (R¹³SO₂L²). The reactive derivativeof sulfonic acid (R¹³SO₂L²) is used in 0.1 to 10 equivalents, preferably0.3 to 3 equivalents, relative to compound (III-2). In the presentmethod, the reaction is generally carried out in the presence of a base,which is not always essential. As the base, those similar to the baseexemplified in Scheme 1 can be used. A base may be used in 0.01 to 10equivalents, preferably 0.03 to 5 equivalents, relative to Compound(III-2). This reaction is advantageously carried out using a solventinert to the reaction. As the solvent, those similar to the solventsexemplified in Scheme 1 can be used. The reaction time is generally 1min to 200 hr, preferably 10 min to 100 hr. The reaction temperature isgenerally −100° C. to 250° C., preferably −78° C. to 200° C. Thereactive derivative of sulfonic acid (R¹³SO₂L²) may be commerciallyavailable, or can be produced according to a method known per se, forexample, the methods described in “Advanced Organic Chemistry, 4th Ed.”(Jerry March), “Comprehensive Organic Transformations, 2nd Ed.” (RichardC. Larock) and the like or a method analogous thereto.

[Production Method 10]

Compound (V-5) shown in Schemes 6 and 7 can be obtained, for example, bythe method described in WO00/23450 or a method analogous thereto and thelike.

wherein each symbol is as defined above.

Compound (V-5) can be produced by reacting compound (VII-2) withcarbonyl derivative (L⁴CHR^(2b)C(O)R^(1b)). A carbonyl derivative isused in 0.1 to 10 equivalents, preferably 0.3 to 5 equivalents, relativeto compound (VII-2). A base may be used in 0.1 to 10 equivalents,preferably 0.3 to 5 equivalents, relative to compound (VII-2). As thebase, those similar to the bases exemplified in Scheme 5 can be used.This reaction is advantageously carried out using a solvent inert to thereaction. As the solvent, those similar to the solvents exemplified inScheme 1 can be used. The reaction time is generally 1 min to 200 hr,preferably 10 min to 100 hr. The reaction temperature is generally −100°C. to 250° C., preferably −78° C. to 200° C. The carbonyl derivative(L⁴CHR^(2b)C(O)R^(1b)) may be commercially available, or can be producedaccording to a method known per se, for example, the methods describedin “Advanced Organic Chemistry, 4th Ed.” (Jerry March), “ComprehensiveOrganic Transformations, 2nd Ed.” (Richard C. Larock) and the like or amethod analogous thereto.

[Production Method 11]

Compound (II) can also be produced by the method shown in Scheme 11.Compounds (IX-1), (IX-2) and (IX-3) are encompassed in compound (III),and compounds (II-7), (II-8), (II-9), (II-10), (II-11), (II-12) and(II-13) are encompassed in compound (II).

wherein R¹⁶ is an optionally substituted aryl or optionally substitutedheterocyclic group, R¹⁷ is an optionally substituted alkyl or optionallysubstituted cycloalkyl, and other symbols are as defined above.

R¹⁶ is a group to be, as R¹⁶NH—, the “optionally substituted arylamino”or “optionally substituted heterocyclylamino” exemplified as apreferable substituent for the aforementioned R¹.

R¹⁷ is a group to be, as R¹⁷CONH—, the “optionally substitutedalkylcarbonylamino” or “optionally substituted cycloalkylcarbonylamino”exemplified as a preferable substituent for the aforementioned R¹.

In Method Q, compound (IX-1) is produced by first reacting compound(V-6) with compound (VI-2) in the presence of a base to give compound(VIII-1), and then reducing the nitro group of compound (VIII-1).Compound (VI-2) is used in 0.1 to 10 equivalents, preferably 0.3 to 3equivalents, relative to compound (V-6). As the base, those similar tothe base exemplified in Scheme 1 can be used. A base is used in 1 to 30equivalents, preferably 1 to 10 equivalents, relative to compound (V-6).This reaction is advantageously carried out using a solvent inert to thereaction. As the solvent, those similar to the solvents exemplified inScheme 1 can be used. The reaction time is generally 1 min to 200 hr,preferably 10 min to 100 hr. The reaction temperature is generally −100°C. to 250° C., preferably −78° C. to 200° C. Compound (VI-2) may becommercially available, or can be produced by a method known per se. Theobtained compound (VIII-1) can be used in the form of a reaction mixtureor a crude product for the next reaction. It may be used for the nextreaction after isolation and purification from the reaction mixtureaccording to a conventional method. The nitro group can be reducedaccording to a method known per se, for example, the method described inthe fourth series of experimental chemistry, vol. 20, 279-280 and thelike, or a method analogous thereto.

In Method R, compound (IX-1) is produced by reacting compound (V-6) withcompound (VI-3) in the presence of a base. Compound (VI-3) is used in0.1 to 10 equivalents, preferably 0.3 to 3 equivalents, relative tocompound (V-6). As the base, those similar to the base exemplified inScheme 1 can be used. A base is used in 1 to 30 equivalents, preferably1 to 10 equivalents, relative to compound (V-6). This reaction isadvantageously carried out using a solvent inert to the reaction. As thesolvent, those similar to the solvents exemplified in Scheme 1 can beused. The reaction time is generally 1 min to 200 hr, preferably 10 minto 100 hr. The reaction temperature is generally −100° C. to 250° C.,preferably −78° C. to 200° C. Compound (VI-3) may be commerciallyavailable, or can be produced by a method known per se.

In Method S, compound (IX-2) is produced by reacting compound (IX-1)with a compound represented by the formula R¹⁰C(O)L². The compoundrepresented by the formula R¹⁰C(O)L² is used in 0.1 to 10 equivalents,preferably 0.3 to 3 equivalents, relative to compound (IX-1). A base maybe used in 0.01 to 10 equivalents, preferably 0.03 to 5 equivalents,relative to compound (IX-1). As the base, those similar to the baseexemplified in Scheme 1 can be used. This reaction is advantageouslycarried out using a solvent inert to the reaction. As the solvent, thosesimilar to the solvents exemplified in Scheme 1 can be used. Thereaction time is generally 1 min to 200 hr, preferably 10 min to 100 hr.The reaction temperature is generally −100° C. to 250° C. preferably−78° C. to 200° C. The compound represented by the formula R¹⁰C(O)L² maybe commercially available, or can be produced according to a methodknown per se, for example, the methods described in “Advanced OrganicChemistry, 4th Ed.” (Jerry March), “Comprehensive OrganicTransformations, 2nd Ed.” (Richard C. Larock) and the like or a methodanalogous thereto.

In Method T, compound (IX-2) is produced by reacting compound (IX-1)with carboxylic acid (R¹⁰CO₂H) in the presence of a condensing agent.When compound (IX-1) is reacted with carboxylic acid (R¹⁰CO₂H) in thepresence of a condensing agent, carboxylic acid (R¹⁰CO₂H) is used in 0.1to 10 equivalents, preferably 0.3 to 3 equivalents, relative to compound(IX-1). As the condensing agent, for example,1-ethyl-1-(3-dimethylaminopropyl)carbodiimide hydrochloride,1,3-dicyclohexylcarbodiimide, diethyl cyanophosphate, diphenylphosphorylazide, 1,1′-carbonyldiimidazole,benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate,O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate,O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate and the like can be used. These condensing agentsare used in 1 to 10 equivalents, preferably 1 to 5 equivalents, relativeto compound (IX-1). Where necessary, a suitable condensation promoter(e.g., 1-hydroxybenzotriazole, N-hydroxysuccinimide etc.) can be used.These condensation promoters are used in 0.1 to 10 equivalents,preferably 0.3 to 3 equivalents, relative to compound (IX-1). Thisreaction may proceed more smoothly when a base is added. As the base,those similar to the base exemplified in Scheme 1 can be used. A base isused in 0.01 to 10 equivalents, preferably 0.03 to 5 equivalents,relative to Compound (IX-1). This reaction is advantageously carried outusing a solvent inert to the reaction. As the solvent, those similar tothe solvents exemplified in Scheme 1 can be used. The reaction time isgenerally 1 min to 200 hr, preferably 10 min to 100 hr. The reactiontemperature is generally −100° C. to 250° C., preferably −78° C. to 200°C. Carboxylic acid (R¹⁰CO₂H) may be commercially available, or can beproduced according to a method known per se, for example, the methodsdescribed in “Advanced Organic Chemistry, 4th Ed.” (Jerry March),“Comprehensive Organic Transformations, 2nd Ed.” (Richard C. Larock) andthe like or a method analogous thereto.

In Method U, compound (IX-3) is produced by treating compound (IX-2)with a base or acid. As the base, for example, sodium hydroxide,potassium hydroxide, cesium hydroxide, barium hydroxide and the like canbe mentioned. A base is used in 0.01 to 10 equivalents, preferably 0.03to 5 equivalents, relative to compound (IX-2). As the acid, for example,hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid,trifluoroacetic acid and the like can be used. An acid is used in 0.1 to20 equivalents, preferably 0.3 to 10 equivalents, relative to compound(IX-2). This reaction is advantageously carried out using a solventinert to the reaction. As the solvent, those similar to the solventsexemplified in Scheme 1 can be used.

In Method V, compound (II-7) is produced by reacting compound (IX-3)with diphenylphosphoryl azide in the presence of a base.Diphenylphosphoryl azide is used in 0.1 to 10 equivalents, preferably0.3 to 5 equivalents, relative to compound (IX-3). As the base, thosesimilar to the bases exemplified in Scheme 1 can be used. As the basefor this method, for example, triethylamine, N-ethyldiisopropylamine,N-methylmorpholine, pyridine and the like are preferable. As the solventfor this reaction, those similar to the solvents exemplified in Scheme 1can be used. For example, alcohols such as methanol, ethanol,2-propanol, 2-methyl-2-propanol and the like are preferable. Thereaction time is generally 1 min to 200 hr, preferably 10 min to 100 hr.The reaction temperature is generally −100° C. to 250° C., preferably−78° C. to 200° C.

In Method W, compound (II-8) is produced by treating compound (II-7)with a base or acid. As the base, for example, sodium hydroxide,potassium hydroxide, cesium hydroxide, barium hydroxide and the like canbe mentioned. A base is used in 0.01 to 10 equivalents, preferably 0.03to 5 equivalents, relative to compound (II-7). As the acid, for example,hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid,trifluoroacetic acid and the like can be used. An acid is used in 0.1 to20 equivalents, preferably 0.3 to 10 equivalents, relative to compound(II-7). This reaction is advantageously carried out using a solventinert to the reaction. As the solvent, those similar to the solventsexemplified in Scheme 1 can be used.

In Method X, compound (II-9) is produced by reacting compound (II-8)with a compound represented by the formula R¹⁵C(O)L². The compoundrepresented by the formula R¹⁵C(O)L² is used in 0.1 to 10 equivalents,preferably 0.3 to 3 equivalents, relative to compound (II-8). The basemay be used in 0.01 to 10 equivalents, preferably 0.03 to 5 equivalents,relative to compound (II-8). As the base, those similar to the baseexemplified in Scheme 1 can be used. This reaction is advantageouslycarried out using a solvent inert to the reaction. As the solvent, thosesimilar to the solvents exemplified in Scheme 1 can be used. Thereaction time is generally 1 min to 200 hr, preferably 10 min to 100 hr.The reaction temperature is generally −100° C. to 250° C., preferably−78° C. to 200° C. The compound represented by the formula R¹⁵C(O)L² maybe commercially available, or can be produced according to a methodknown per se, for example, the methods described in “Advanced OrganicChemistry, 4th Ed.” (Jerry March), “Comprehensive OrganicTransformations, 2nd Ed.” (Richard C. Larock) and the like or a methodanalogous thereto.

In Method Y, compound (II-9) is produced by reacting compound (II-8)with carboxylic acid (R¹⁵CO₂H) in the presence of a condensing agent.When compound (II-8) is reacted with carboxylic acid (R¹⁵CO₂H) in thepresence of a condensing agent, carboxylic acid (R¹⁵CO₂H) is used in 0.1to 10 equivalents, preferably 0.3 to 3 equivalents, relative to compound(II-8). As the condensing agent, for example,1-ethyl-1-(3-dimethylaminopropyl)carbodiimide hydrochloride,1,3-dicyclohexylcarbodiimide, diethyl cyanophosphate, diphenylphosphorylazide, 1,1′-carbonyldiimidazole,benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate,O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate,O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate and the like can be used. These condensing agentsare used in 1 to 10 equivalents, preferably 1 to 5 equivalents, relativeto compound (II-8). Where necessary, a suitable condensation promoter(e.g., 1-hydroxybenzotriazole, N-hydroxysuccinimide etc.) can be used.These condensation promoters are used in 0.1 to 10 equivalents,preferably 0.3 to 3 equivalents, relative to compound (II-8). Thisreaction may proceed more smoothly when a base is added. As the base,those similar to the base exemplified in Scheme 1 can be used. The baseis used in 0.01 to 10 equivalents, preferably 0.03 to 5 equivalents,relative to compound (II-8). This reaction is advantageously carried outusing a solvent inert to the reaction. As the solvent, those similar tothe solvents exemplified in Scheme 1 can be used. The reaction time isgenerally 1 min to 200 hr, preferably 10 min to 100 hr. The reactiontemperature is generally −100° C. to 250° C., preferably −78° C. to 200°C. Carboxylic acid (R¹⁵CO₂H) may be commercially available, or can beproduced according to a method known per se, for example, the methodsdescribed in “Advanced Organic Chemistry, 4th Ed.” (Jerry March),“Comprehensive Organic Transformations, 2nd Ed.” (Richard C. Larock) andthe like or a method analogous thereto.

In Method Z, compound (II-10) is produced by reacting compound (II-8)with a compound represented by the formula R¹⁶L¹ in the presence of abase. The compound represented by the formula R¹⁶L¹ is used in 0.1 to 10equivalents, preferably 0.3 to 3 equivalents, relative to compound(II-8). As the base, those similar to the base exemplified in Scheme 1can be used. This reaction is advantageously carried out using a solventinert to the reaction. As the solvent, those similar to the solventsexemplified in Scheme 1 can be used. The reaction time is generally 1min to 200 hr, preferably 10 min to 100 hr. The reaction temperature isgenerally −100° C. to 250° C., preferably −78° C. to 200° C. Thecompound represented by the formula R¹⁶L¹ may be commercially available,or can be produced according to a method known per se, for example, themethod described in “Advanced Organic Chemistry, 4th Ed.” (Jerry March),“Comprehensive Organic Transformations, 2nd Ed.” (Richard C. Larock) andthe like, or a method analogous thereto.

In Method Aa, compound (II-12) is produced by treating compound (II-11)with a base or acid. As the base, for example, sodium hydroxide,potassium hydroxide, cesium hydroxide, barium hydroxide and the like canbe mentioned. A base is used in 0.01 to 10 equivalents, preferably 0.03to 5 equivalents, relative to compound (II-11). As the acid, forexample, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuricacid, trifluoroacetic acid and the like can be used. An acid is used in0.1 to 20 equivalents, preferably 0.3 to 10 equivalents, relative tocompound (II-11). This reaction is advantageously carried out using asolvent inert to the reaction. As the solvent, those similar to thesolvents exemplified in Scheme 1 can be used.

In Method Ab, compound (II-13) is produced by reacting compound (II-12)with a compound represented by the formula R¹⁵C(O)L². The compoundrepresented by the formula R¹⁵C(O)L² is used in 0.1 to 10 equivalents,preferably 0.3 to 3 equivalents, relative to compound (II-12). A basemay be used in 0.01 to 10 equivalents, preferably 0.03 to 5 equivalents,relative to compound (II-12). As the base, those similar to the baseexemplified in Scheme 1 can be used. This reaction is advantageouslycarried out using a solvent inert to the reaction. As the solvent, thosesimilar to the solvents exemplified in Scheme 1 can be used. Thereaction time is generally 1 min to 200 hr, preferably 10 min to 100 hr.The reaction temperature is generally −100° C. to 250° C., preferably−78° C. to 200° C. a compound represented by the formula R¹⁵C(O)L² maybe commercially available, or can be produced according to a methodknown per se, for example, the methods described in “Advanced OrganicChemistry, 4th Ed.” (Jerry March), “Comprehensive OrganicTransformations, 2nd Ed.” (Richard C. Larock) and the like or a methodanalogous thereto.

In Method Ac, (II-13) is produced by reacting compound (II-12) withcarboxylic acid (R¹⁵CO₂H) in the presence of a condensing agent. Whencompound (II-12) is reacted with carboxylic acid (R¹⁵CO₂H) in thepresence of a condensing agent, carboxylic acid (R¹⁵CO₂H) is used in 0.1to 10 equivalents, preferably 0.3 to 3 equivalents, relative to compound(II-12). As the condensing agent, for example,1-ethyl-1-(3-dimethylaminopropyl)carbodiimide hydrochloride,1,3-dicyclohexylcarbodiimide, diethyl cyanophosphate, diphenylphosphorylazide, 1,1′-carbonyldiimidazole,benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate,O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate,O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate and the like can be used. These condensing agentsare used in 1 to 10 equivalents, preferably 1 to 5 equivalents, relativeto compound (II-12). Where necessary, a suitable condensation promoter(e.g., 1-hydroxybenzotriazole, N-hydroxysuccinimide etc.) can be used.These condensation promoters are used in 0.1 to 10 equivalents,preferably 0.3 to 3 equivalents, relative to compound (II-12). Thisreaction may proceed more smoothly when a base is added. As the base,those similar to the base exemplified in Scheme 1 can be used. The baseis used in 0.01 to 10 equivalents, preferably 0.03 to 5 equivalents,relative to compound (II-12). This reaction is advantageously carriedout using a solvent inert to the reaction. As the solvent, those similarto the solvents exemplified in Scheme 1 can be used. The reaction timeis generally 1 min to 200 hr, preferably 10 min to 100 hr. The reactiontemperature is generally −100° C. to 250° C., preferably −78° C. to 200°C. Carboxylic acid (R¹⁵CO₂H) may be commercially available, or can beproduced according to a method known per se, for example, the methodsdescribed in “Advanced Organic Chemistry, 4th Ed.” (Jerry March),“Comprehensive Organic Transformations, 2nd Ed.” (Richard C. Larock) andthe like or a method analogous thereto.

[Production Method 12]

Compound (II) wherein Ya is substituted by an optionally substitutedaminocarbonyl group, and optionally further substituted can also beproduced, for example, by the method shown in Scheme 12. Compounds(II-14), (II-15) and (II-16) are encompassed in compound (II).

wherein R¹⁸ is an alkyl group, and other symbols are as defined above.

As the alkyl for R¹⁸, for example, methyl, ethyl, propyl, isopropyl,tert-butyl and the like can be mentioned.

In Method Ad, compound (II-14) can be produced by reacting compound(V-1) with compound (VI-7). Compound (VI-7) is used in 0.1 to 10equivalents, preferably 0.3 to 3 equivalents, relative to compound(V-1). Where necessary, a base may be added. As the base, inorganic baseor organic base and the like can be used. Specifically, for example,sodium carbonate, potassium carbonate, cesium carbonate, sodiumbicarbonate, triethylamine, N-ethyldiisopropylamine, N-methylmorpholine,1,8-diazabicyclo[5.4.0]undec-7-ene, pyridine, 4-(dimethylamino)pyridine,N,N-dimethylaniline, sodium methoxide, sodium ethoxide, potassiumtert-butoxide, sodium hydride, sodium amide, lithium diisopropylamideand the like can be used. These bases are used in 1 to 30 equivalents,preferably 1 to 10 equivalents, relative to compound (V-1). Thisreaction is advantageously carried out using a solvent inert to thereaction. As the solvent, those similar to the solvents exemplified inScheme 1 can be used. The reaction time is generally 1 min to 200 hr,preferably 10 min to 100 hr. The reaction temperature is generally −100°C. to 250° C., preferably −78° C. to 200° C. Compound (VI-7) may becommercially available, or can be produced according to a method knownper se, for example, the methods described in “Advanced OrganicChemistry, 4th Ed.” (Jerry March), “Comprehensive OrganicTransformations, 2nd Ed.” (Richard C. Larock) and the like or a methodanalogous thereto. The reaction may be carried out using a microwavesynthesizer.

In Method Ae, compound (II-15) is produced by treating compound (II-14)with a base or acid. As the base, for example, sodium hydroxide,potassium hydroxide, cesium hydroxide, barium hydroxide and the like canbe mentioned. A base is used in 0.01 to 10 equivalents, preferably 0.03to 5 equivalents, relative to compound (II-14). As the acid, forexample, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuricacid, trifluoroacetic acid and the like can be used. An acid is used in0.1 to 20 equivalents, preferably 0.3 to 10 equivalents, relative tocompound (II-14). This reaction is advantageously carried out using asolvent inert to the reaction. As the solvent, those similar to thesolvents exemplified in Scheme 1 can be used.

In Method Af, compound (II-16) is produced by reacting compound (II-15)with an amine derivative (R¹¹R¹²NH) under a condensing agent. The aminederivative (R¹¹R¹²NH) is used in 0.1 to 10 equivalents, preferably 0.3to 3 equivalents, relative to compound (II-15). As the condensing agent,for example, 1-ethyl-1-(3-dimethylaminopropyl)carbodiimidehydrochloride, 1,3-dicyclohexylcarbodiimide, diethyl cyanophosphate,diphenylphosphoryl azide, 1,1′-carbonyldiimidazole,benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate,O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate,O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate and the like can be used. These condensing agentsare used in 1 to 10 equivalents, preferably 1 to 5 equivalents, relativeto compound (II-15). Where necessary, a suitable condensation promoter(e.g., 1-hydroxybenzotriazole, N-hydroxysuccinimide etc.) can be used.These condensation promoters are used in 0.1 to 10 equivalents,preferably 0.3 to 3 equivalents, relative to compound (II-15). Thisreaction may proceed more smoothly when a base is added. As the base,those similar to the base exemplified in Scheme 1 can be used. Thesebases are used in 0.01 to 10 equivalents, preferably 0.03 to 5equivalents, relative to compound (II-15). This reaction isadvantageously carried out using a solvent inert to the reaction. As thesolvent, those similar to the solvents exemplified in Scheme 1 can beused. The reaction time is generally 1 min to 200 hr, preferably 10 minto 100 hr. The reaction temperature is generally −100° C. to 250° C.,preferably −78° C. to 200° C. The amine derivative (R¹¹R¹²NH) may becommercially available, or can be produced according to a method knownper se, for example, the methods described in “Advanced OrganicChemistry, 4th Ed.” (Jerry March), “Comprehensive OrganicTransformations, 2nd Ed.” (Richard C. Larock) and the like or a methodanalogous thereto.

[Production Method 13]

Compound (II) wherein Ya is substituted by optionally substituted amide,and is optionally further substituted, can also be produced by themethod shown in Production Method 2, as well as, for example, Scheme 13.Compounds (II-17) and (II-18) are encompassed in compound (II).

wherein L⁵ is a leaving group, R¹⁹ and R²⁰ are, as —NR¹⁹C(O)R²⁰, each agroup to be amino substituted by the “C₁₋₈ alkyl-carbonyl, C₂₋₈alkenyl-carbonyl, C₂₋₈ alkynyl-carbonyl, C₃₋₈ cycloalkyl-carbonyl, C₃₋₆cycloalkenyl-carbonyl, C₆₋₁₈ aryl-carbonyl, C₆₋₁₈ aryl-C₁₋₄alkyl-carbonyl or heterocyclyl-carbonyl, each of which is optionallysubstituted” as the substituent on the aforementioned ring Y, and othersymbols are as defined above.

As the leaving group for L⁵, a halogen atom can be used.

In Method Ag, compound (II-17) can be produced by reacting compound(V-1) with compound (VI-8). Compound (VI-8) is used in 0.1 to 10equivalents, preferably 0.3 to 3 equivalents, relative to compound(V-1). Where necessary, a base may be added. As the base, inorganic baseor organic base and the like can be used. Specifically, for example,sodium carbonate, potassium carbonate, cesium carbonate, sodiumbicarbonate, triethylamine, N-ethyldiisopropylamine, N-methylmorpholine,1,8-diazabicyclo[5.4.0]undec-7-ene, pyridine, 4-(dimethylamino)pyridine,N,N-dimethylaniline, sodium methoxide, sodium ethoxide, potassiumtert-butoxide, sodium hydride, sodium amide, lithium diisopropylamideand the like can be mentioned. These bases are used in 1 to 30equivalents, preferably 1 to 10 equivalents, relative to compound (V-1).This reaction is advantageously carried out using a solvent inert to thereaction. As the solvent, those similar to the solvents exemplified inScheme 1 can be used. The reaction time is generally 1 min to 200 hr,preferably 10 min to 100 hr. The reaction temperature is generally −100°C. to 250° C., preferably −78° C. to 200° C. Compound (VI-8) may becommercially available, or can be produced according to a method knownper se, for example, the method described in “Advanced OrganicChemistry, 4th Ed.” (Jerry March), “Comprehensive OrganicTransformations, 2nd Ed.” (Richard C. Larock) and the like or a methodanalogous thereto. The reaction may be carried out using a microwavesynthesizer.

In Method Ah, compound (II-18) can be produced by reacting compound(II-17) with compound (VII-3) under a copper catalyst. Compound (II-3)is used in 0.1 to 10 equivalents, preferably 0.3 to 3 equivalents,relative to compound (VII-17). As the copper catalyst, for example,copper iodide and copper (II) trifluoromethanesulfonate can be used.Where necessary, a base may be added. As the base, for example, sodiumcarbonate, potassium carbonate, cesium carbonate, sodium bicarbonate,sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodiumtert-butoxide, potassium phosphate tribasic,trans-1,2-cyclohexanediamine, 1,10-phenanthrolin,N,N-dimethylethylenediamine and the like can be used. These bases areused in 1 to 30 equivalents, preferably 1 to 10 equivalents, relative tocompound (II-17). This reaction is advantageously carried out using asolvent inert to the reaction. As the solvent, those similar to thesolvents exemplified in Scheme 1 can be used. The reaction time isgenerally 1 min to 200 hr, preferably 10 min to 100 hr. The reactiontemperature is generally −100° C. to 250° C., preferably −78° C. to 200°C. Compound (VII-3) may be commercially available, or can be producedaccording to a method known per se, for example, the methods describedin “Advanced Organic Chemistry, 4th Ed.” (Jerry March), “ComprehensiveOrganic Transformations, 2nd Ed.” (Richard C. Larock) and the like or amethod analogous thereto.

[Production Method 14]

Compound (II) wherein Ya is substituted by optionally substitutedacylthioureido and optionally further substituted can also be produced,for example, by the method shown in Scheme 14. Compound (II-19) isencompassed in compound (II).

wherein R²¹ is, as —C(S)NHC(O)R²¹, a group that becomes the “aminosubstituted by optionally substituted aminothiocarbonyl” as thesubstituent on the aforementioned ring Y, and other symbols are asdefined above.

Compound (II-19) can be produced by reacting compound (II-2) with anacylthiocyanate derivative (R²¹C(O)NCS). The acylthiocyanate derivative(R²¹C(O)NCS) is used in 0.1 to 10 equivalents, preferably 0.5 to 5equivalents, relative to compound (II-19). This reaction isadvantageously carried out using a solvent inert to the reaction. As thesolvent, those similar to the solvents exemplified in Scheme 1 can beused. The reaction time is generally 1 min to 200 hr, preferably 10 minto 100 hr. The reaction temperature is generally −100° C. to 250° C.,preferably −78° C. to 200° C. The acylthiocyanate derivative(R²¹C(O)NCS) may be commercially available, or can be produced accordingto a method known per se.

It is also possible to produce a compound encompassed in the scope ofthe present invention by subjecting compounds (I)-(IV) (e.g., compound(II) and compound (III) obtained by the above-mentioned method) tointroduction of substituents and functional group conversion by a meansknown per se. For the substituent conversion, a known conventionalmethod can be used. For example, conversion to carboxy by hydrolysis ofester, conversion to carbamoyl by amidation of carboxy, conversion tohydroxymethyl by reduction of carboxy, conversion to alcohol compound byreduction or alkylation of carbonyl, reductive amination of carbonyl,oximation of carbonyl, acylation, ureation, sulfonylation or alkylationof amino, substitution and amination of active halogen by amine,amination by reduction of nitro, alkylation of hydroxy, substitution andamination of hydroxy and the like can be mentioned. When a reactivesubstituent that causes non-objective reaction is present during theintroduction of substituents and conversion of functional groups, aprotecting group is introduced in advance as necessary into the reactivesubstituent by a means known per se, and the protecting group is removedby a means known per se after the objective reaction, whereby a compoundwithin the scope of the present invention can also be produced.

Compounds (I)-(IV) (e.g., compound (II) and compound (III) obtained bythe above-mentioned method) can be isolated and purified by a meansknown per se, such as phase transfer, concentration, solvent extraction,fractionation, liquid conversion, crystallization, recrystallization,chromatography and the like. When compounds (I)-(IV) are obtained asfree compounds, they can be converted to desired salts by a method knownper se or a modification thereof; conversely, when the compounds areobtained as salts, they can be converted to free forms or other desiredsalts by a method known per se or a modification thereof.

Compounds (I)-(IV) (hereinafter to be also referred to as compound (I)and the like) may be used as prodrugs. A prodrug of compound (I) and thelike means a compound which is converted to compound (I) and the like bya reaction due to an enzyme, a gastric acid, etc. under thephysiological condition in the living body, that is, a compound which isconverted to compound (I) and the like by oxidation, reduction,hydrolysis, etc. due to an enzyme; a compound which is converted tocompound (I) and the like by hydrolysis etc. due to gastric acid, andthe like.

A prodrug of compound (I) and the like may be a compound obtained bysubjecting an amino in compound (I) and the like to an acylation,alkylation or phosphorylation (e.g., a compound obtained by subjectingan amino in compound (I) and the like to an eicosanoylation,alanylation, pentylaminocarbonylation,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylation,tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation ortert-butylation); a compound obtained by subjecting a hydroxy incompound (I) and the like to an acylation, alkylation, phosphorylationor boration (e.g., a compound obtained by subjecting an hydroxy incompound (I) and the like to an acetylation, palmitoylation,propanoylation, pivaloylation, succinylation, fumarylation, alanylationor dimethylaminomethylcarbonylation); a compound obtained by subjectinga carboxy in compound (I) and the like to an esterification or amidation(e.g., a compound obtained by subjecting a carboxy in compound (I) andthe like to an ethyl esterification, phenyl esterification,carboxymethyl esterification, dimethylaminomethyl esterification,pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification,phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methylesterification, cyclohexyloxycarbonylethyl esterification ormethylamidation) and the like. Any one of these compounds can beproduced from compound (I) and the like by a method known per se.

A prodrug of compound (I) and the like may also be one which isconverted into compound (I) and the like under a physiologicalcondition, such as those described in IYAKUHIN no KAIHATSU (Developmentof Pharmaceuticals), Vol. 7, Design of Molecules, p. 163-198, Publishedby HIROKAWA SHOTEN (1990).

When compound (I) and the like has isomers such as optical isomer,stereoisomer, positional isomer, rotational isomer and the like, and anyisomers and mixtures are encompassed in compound (I) and the like. Forexample, when compound (I) and the like has an optical isomer, anoptical isomer separated from a racemate is also encompassed in compound(I) and the like. These isomers can be obtained as independent productsby a synthesis means or a separation means (concentration, solventextraction, column chromatography, recrystallization and the like) knownper se.

The compound (I) and the like may be a crystal, and both a singlecrystal and crystal mixtures are encompassed in compound (I) and thelike. Crystals can be produced by crystallization according tocrystallization methods known per se.

The compound (I) and the like may be a co-crystal.

The compound (I) and the like may be a solvate (e.g., hydrate etc.) or anon-solvate, both of which are encompassed in compound (I) and the like.

A compound labeled with an isotope (e.g., ³H, ¹⁴C, ³⁵S, ¹²⁵I etc.) isalso encompassed in compound (I) and the like.

Compounds (I)-(IV) of the present invention, a salt thereof and aprodrug thereof (hereinafter sometimes to be abbreviated as the compoundof the present invention) have, for example, phosphorylation-inhibitoryactivity against a kinase having such phosphorylating action. As usedherein, kinase encompasses not only a substance having a phosphorylatingaction by itself as a whole, but also a substance a part of which has aphosphorylating action. The phosphorylating action possessed by kinasesencompasses both a phosphorylating action on its own and that on othersubstances.

Examples of kinase include vascular endothelial growth factor receptor(VEGFR), platelet-derived growth factor receptor (PDGFR), Raf and thelike. Examples of vascular endothelial growth factor receptor (VEGFR)include vascular endothelial growth factor receptor 1 (VEGFR1, Flt-1),vascular endothelial growth factor receptor 2 (VEGFR2, KDR, Flk-1),vascular endothelial growth factor receptor 3 (VEGFR3, Flt-4) and thelike. Of these, vascular endothelial growth factor receptor 2 (VEGFR2)is preferable. Examples of platelet-derived growth factor receptor(PDGFR) include platelet-derived growth factor receptor α (PDGFRα),platelet-derived growth factor receptor β (PDGFRβ) and the like.Examples of Raf include A-Raf, B-Raf, C-Raf and the like. Particularly,as kinase, vascular endothelial growth factor receptor 2 (VEGFR2),platelet-derived growth factor receptor (PDGFR) and Raf are preferable.

Besides these, as kinase, tyrosine Kinase with Ig and EGF homologydomains 2 (TIE2), fibroblast growth factor receptor 1 (FGFR1),fibroblast growth factor receptor 2 (FGFR2), fibroblast growth factorreceptor 3 (FGFR3), fibroblast growth factor receptor 4 (FGFR4), stemcell factor receptor (c-Kit), Aurora A, Aurora B, CDK, MEK1, MEK2, Akt,ERK, MAPK, Src, MET, epithelial cell growth factor receptor (EGFR),human epithelial growth factor receptor 2 (HER2), human epithelialgrowth factor receptor 4 (HER4), Abl, Fgr, Fms and the like can also beused.

For example, the vascular endothelial growth factor receptor 2inhibitory activity of the compound of the present invention can bedetermined according to Test Example 1, the vascular endothelial cellgrowth inhibitory activity can be determined according to Test Example2, the antitumor activity can be determined according to Test Example 3,the platelet-derived growth factor receptor α inhibitory activity can bedetermined according to Test Example 4, the platelet-derived growthfactor receptor β inhibitory activity can be determined according toTest Example 5, and the B-Raf inhibitory activity can be determinedaccording to Test Example 6.

The compound of the present invention particularly shows potentinhibitory activity for vascular endothelial growth factor receptor(VEGFR), and specifically high selectivity for vascular endothelialgrowth factor receptor 2 (VEGFR2, KDR, Flk-1) and potent kinaseinhibitory activity for VEGFR1, PDGFR, and Raf. In addition, since thecompound of the present invention is also superior in the efficacy,pharmacokinetics (absorption, distribution, metabolism, excretion etc.),solubility (water-solubility etc.), interaction with otherpharmaceutical products, safety (acute toxicity, chronic toxicity,genetic toxicity, reproductive toxicity, cardiotoxicity, carcinogenicityetc.) and stability (chemical stability, stability to enzyme etc.), itis useful as a pharmaceutical agent.

Accordingly, the compound of the present invention is useful as a kinaseinhibitor, preferably a vascular endothelial growth factor receptor(VEGFR) inhibitor, a platelet-derived growth factor receptor (PDGFR)inhibitor, a Raf inhibitor, more preferably a vascular endothelialgrowth factor receptor 2 (VEGFR2, KDR, Flk-1) inhibitor for a mammal(e.g., mouse, rat, hamster, rabbit, cat, dog, bovine, sheep, monkey,human etc.). In addition, the compound of the present invention isuseful as an angiogenesis inhibitor or a vascular endothelial cellgrowth inhibitor. The compound of the present invention is used as apharmaceutical agent such as an agent for the prophylaxis or treatmentof diseases possibly affected by a vascular endothelial growth factor,for example, cancer [e.g., colorectal cancer (e.g., familial colorectalcancer, hereditary nonpolyposis colorectal cancer, gastrointestinalstromal tumor, etc.), lung cancer (e.g., non-small cell lung cancer,small cell lung cancer, malignant mesothelioma, etc.), mesothelioma,pancreatic cancer (e.g., pancreatic duct cancer, etc.), gastric cancer(e.g., papillary adenocarcinoma, mucinous adenocarcinoma, adenosquamouscancer, etc.), breast cancer (e.g., invasive ductal carcinoma, ductalcancer in situ, inflammatory breast cancer, etc.), ovarian cancer (e.g.,ovarian epithelial cancer, extragonadal germ cell tumor, ovarian germcell tumor, ovarian low malignant potential tumor, etc.), prostatecancer (e.g., hormone-dependent prostate cancer, non-hormone dependentprostate cancer, etc.), liver cancer (e.g., primary liver cancer,extrahepatic bile duct cancer, etc.), thyroid cancer (e.g., medullarythyroid cancer, etc.), kidney cancer (e.g., renal cell carcinoma, renalpelvis and ureter transitional cell cancer, etc.), uterine cancer, braintumor (e.g., pineal astrocytoma, pilocytic astrocytoma, diffuseastrocytoma, anaplastic astrocytoma, etc.), melanoma, sarcoma, bladdercancer, blood cancer including multiple myeloma etc.], diabeticretinopathy, rheumatoid arthritis, psoriasis, atherosclerosis, Kaposi'ssarcoma, COPD, pain, asthma, endometriosis, nephritis, inflammation suchas osteoarthritis and the like and hypertension, a cancer growthinhibitor, a cancer metastasis suppressor, an apoptosis promoter and thelike. Of these, it is effective, for example, for colorectal cancer,lung cancer, pancreatic cancer, gastric cancer, breast cancer, ovarycancer, prostate cancer, liver cancer, thyroid cancer, kidney cancer,cerebral tumor, melanoma, bladder cancer and blood cancer. Particularly,the compound of the present invention is effective for patients withlung cancer, colorectal cancer, ovary cancer, prostate cancer or kidneycancer.

The compound of the present invention can be administered orally orparenterally as it is or in a mixture with a pharmacologicallyacceptable carrier.

The dosage form of the compound of the present invention for oraladministration is, for example, tablet (including sugar-coated tablet,film-coated tablet), pill, granule, powder, capsule (including softcapsule, microcapsule), syrup, emulsion, suspension and the like, andthe dosage form for parenteral administration is, for example,injection, injecting agent, instillation, suppository and the like. Inaddition, it is effective to make a sustained release preparation bycombining the compound with a suitable base (e.g., polymer of butyricacid, polymer of glycolic acid, copolymer of butyric acid-glycolic acid,a mixture of a polymer of butyric acid and a polymer of glycolic acid,polyglycerol fatty acid ester etc.).

As a method to produce the compound of the present invention in theabove-mentioned dosage form, a known production method generally used inthe pertinent field can be employed. When the above-mentioned dosageform is produced, suitable amounts of additives such as excipient,binder, disintegrant, lubricant, sweetening agent, surfactant,suspending agent, emulsifier and the like, generally used in thepertinent field, are appropriately added as necessary for production.

When the compound of the present invention is prepared into a tablet,for example, it can be produced by adding an excipient, a binder, adisintegrant, a lubricant and the like, and when a pill or a granule isto be prepared, it can be produced by adding an excipient, a binder, adisintegrant and the like. When a powder or a capsule is to be prepared,it can be produced by adding an excipient and the like, when a syrup isto be prepared, it can be produced by adding a sweetener and the like,and when an emulsion or a suspension is to be prepared, it can beproduced by adding a suspending agent, a surfactant, an emulsifier andthe like.

Examples of the excipient include lactose, sucrose, glucose, starch,sucrose, microcrystalline cellulose, powdered glycyrrhiza, mannitol,sodium hydrogencarbonate, calcium phosphate, calcium sulfate and thelike.

Examples of the binder include 5-10 wt % starch liquid paste, 10-20 wt %gum arabic solution or gelatin solution, 1-5 wt % tragacanth solution,carboxymethyl cellulose solution, sodium alginate solution, glycerin andthe like.

Examples of the disintegrant include starch, calcium carbonate and thelike.

Examples of the lubricant include magnesium stearate, stearic acid,calcium stearate, purified talc and the like.

Examples of the sweetener include glucose, fructose, invert sugar,sorbitol, xylitol, glycerin, simple syrup and the like.

Examples of the surfactant include sodium lauryl sulfate, polysorbate80, sorbitan monofatty acid ester, polyoxyl 40 stearate and the like.

Examples of the suspending agent include gum arabic, sodium alginate,sodium carboxymethyl cellulose, methyl cellulose, bentonite and thelike.

Examples of the emulsifier include gum arabic, tragacanth, gelatin,polysorbate 80 and the like.

Furthermore, when the compound of the present invention is produced inthe above-mentioned dosage form, a suitable amount of a coloring agent,a preservative, an aromatic, a corrigent, a stabilizer, a thickeningagent and the like typically used in the field of preparation can beadded on demand.

As the injection, intravenous injection as well as subcutaneousinjection, intracutaneous injection, intramuscular injection,instillation and the like are mentioned, and as the sustained releasepreparation, an iontophoresis transdermal agent and the like arementioned.

Such injections are prepared by methods known per se, or by dissolving,suspending or emulsifying the compound of the present invention in asterilized aqueous or oily liquid. As an aqueous liquid for injection,physiological saline, isotonic solutions containing glucose or otherauxiliary drugs (e.g., D-sorbitol, D-mannitol, sodium chloride and thelike) and the like can be mentioned, and they can be used in combinationwith suitable dissolution aids, such as alcohols (e.g., ethanol),polyalcohols (e.g., propylene glycol, polyethylene glycol), nonionicsurfactants (e.g., polysorbate 80, HCO-50) and the like. As an oilyliquid, sesame oil, soybean oil and the like can be mentioned, which maybe used in combination with dissolution aids such as benzyl benzoate,benzyl alcohol and the like. In addition, buffers (e.g., phosphatebuffer, sodium acetate buffer), soothing agents (e.g., benzalkoniumchloride, procaine hydrochloride and the like), stabilizers (e.g., humanserum albumin, polyethylene glycol and the like), preservatives (e.g.,benzyl alcohol, phenol and the like) and the like can be mentioned. Aprepared injection is generally filled in an ampoule.

While the content of the compound of the present invention in thepharmaceutical agent of the present invention varies depending on theform of the pharmaceutical preparation, it is generally about 0.01 to100 wt %, preferably about 2 to 85 wt %, more preferably about 5 to 70wt %, relative to the entire preparation.

While the content of the additive in the pharmaceutical agent of thepresent invention varies depending on the form of the pharmaceuticalpreparation, it is generally about 1 to 99.9 wt %, preferably about 10to 90 wt %, relative to the entire preparation.

The compound of the present invention is stable and low toxic, and canbe used safely. While the daily dose varies depending on the conditionand body weight of patients, the kind of compound, administration routeand the like, in the case of, for example, oral administration topatients for the treatment of cancer, the daily dose to an adult (bodyweight about 60 kg) is about 1 to 1000 mg, preferably about 3 to 300 mg,more preferably about 10 to 200 mg, as an active ingredient (thecompound of the present invention), which can be given in a singleadministration or administered in 2 or 3 portions a day.

When the compound of the present invention is administered parenterally,it is generally administered in the form of a liquid (e.g., injection).While the dose varies depending on the subject of administration, targetorgan, symptom, administration method and the like, it is, for example,about 0.01 mg to about 100 mg, preferably about 0.01 to about 50 mg,more preferably about 0.01 to about 20 mg, in the form of an injection,relative to 1 kg body weight, which is preferably given by intravenousinjection.

The compound of the present invention can be used concurrently withother drugs. To be specific, the compound of the present invention canbe used together with medicaments such as hormonal therapeutic agents,chemotherapeutic agents, immunotherapeutic agents, pharmaceutical agentsinhibiting the action of cell growth factors or cell growth factorreceptors and the like. In the following, the drugs that can be used incombination with the compound of the present invention are abbreviatedas concomitant drugs.

Examples of the “hormonal therapeutic agents” include fosfestrol,diethylstylbestrol, chlorotrianisene, medroxyprogesterone acetate,megestrol acetate, chlormadinone acetate, cyproterone acetate, danazol,allylestrenol, gestrinone, mepartricin, raloxifene, ormeloxifene,levormeloxifene, anti-estrogens (e.g., tamoxifen citrate, toremifenecitrate, and the like), pill preparations, mepitiostane, testrolactone,aminoglutethimide, LH-RH agonists (e.g., goserelin acetate, buserelin,leuprorelin, and the like), droloxifene, epitiostanol, ethinylestradiolsulfonate, aromatase inhibitors (e.g., fadrozole hydrochloride,anastrozole, retrozole, exemestane, vorozole, formestane, and the like),anti-androgens (e.g., flutamide, bicartamide, nilutamide, and the like),5α-reductase inhibitors (e.g., finasteride, epristeride, and the like),aderenal cortex hormone drugs (e.g., dexamethasone, prednisolone,betamethasone, triamcinolone, and the like), androgen synthesisinhibitors (e.g., abiraterone, and the like), retinoid and drugs thatretard retinoid metabolism (e.g., liarozole, and the like), and thelike.

Examples of the “chemotherapeutic agents” include alkylating agents,antimetabolites, anticancer antibiotics, plant-derived anticanceragents, and the like.

Examples of the “alkylating agents” include nitrogen mustard, nitrogenmustard-N-oxide hydrochloride, chlorambutyl, cyclophosphamide,ifosfamide, thiotepa, carboquone, improsulfan tosylate, busulfan,nimustine hydrochloride, mitobronitol, melphalan, dacarbazine,ranimustine, sodium estramustine phosphate, triethylenemelamine,carmustine, lomustine, streptozocin, pipobroman, etoglucid, carboplatin,cisplatin, miboplatin, nedaplatin, oxaliplatin, altretamine,ambamustine, dibrospidium hydrochloride, fotemustine, prednimustine,pumitepa, ribomustin, temozolomide, treosulphan, trophosphamide,zinostatin stimalamer, adozelesin, cystemustine, bizelesin, DDSpreparations thereof, and the like.

Examples of the “antimetabolites” include mercaptopurine,6-mercaptopurine riboside, thioinosine, methotrexate, pemetrexed,enocitabine, cytarabine, cytarabine ocfosfate, ancitabine hydrochloride,5-FU drugs (e.g., fluorouracil, tegafur, UFT, doxifluridine, carmofur,gallocitabine, emmitefur, capecitabine, and the like), aminopterine,nelzarabine, leucovorin calcium, tabloid, butocine, folinate calcium,levofolinate calcium, cladribine, emitefur, fludarabine, gemcitabine,hydroxycarbamide, pentostatin, piritrexim, idoxuridine, mitoguazone,thiazophrine, ambamustine, bendamustine, DDS preparations thereof, andthe like.

Examples of the “anticancer antibiotics” include actinomycin-D,actinomycin-C, mitomycin-C, chromomycin-A3, bleomycin hydrochloride,bleomycin sulfate, peplomycin sulfate, daunorubicin hydrochloride,doxorubicin hydrochloride, aclarubicin hydrochloride, pirarubicinhydrochloride, epirubicin hydrochloride, neocarzinostatin, mithramycin,sarcomycin, carzinophilin, mitotane, zorubicin hydrochloride,mitoxantrone hydrochloride, idarubicin hydrochloride, DDS preparationsthereof, and the like.

Examples of the “plant-derived anticancer agents” include etoposide,etoposide phosphate, vinblastine sulfate, vincristine sulfate, vindesinesulfate, teniposide, paclitaxel, docetaxel, vinorelbine, DDSpreparations thereof, and the like.

Examples of the “immunotherapeutic agents (BRM)” include picibanil,krestin, sizofuran, lentinan, ubenimex, interferons, interleukins,macrophage colony-stimulating factor, granulocyte colony-stimulatingfactor, erythropoietin, lymphotoxin, BCG vaccine, Corynebacteriumparvum, levamisole, polysaccharide K, procodazole, anti-CTLA4 antibody,and the like.

Example of the “cell growth factor” in the “pharmaceutical agentsinhibiting the action of cell growth factors or cell growth factorreceptors” include any substances that promote cell proliferation, whichare normally peptides having not more than 20,000 molecular weight thatare capable of exhibiting their activity at low concentrations bybinding to a receptor, including (1) EGF (epidermal growth factor) orsubstances possessing substantially the same activity as EGF [e.g.,TGFα, and the like], (2) insulin or substances possessing substantiallythe same activity as insulin [e.g., insulin, IGF (insulin-like growthfactor)-1, IGF-2, and the like], (3) FGF (fibroblast growth factor) orsubstances possessing substantially the same activity as FGF [e.g.,acidic FGF, basic FGF, KGF (keratinocyte growth factor), FGF-10, and thelike], (4) other cell growth factors [e.g., CSF (colony stimulatingfactor), EPO (erythropoietin), IL-2 (interleukin-2), NGF (nerve growthfactor), PDGF (platelet-derived growth factor), TGFβ (transforminggrowth factorβ), HGF (hepatocyte growth factor), VEGF (vascularendothelial growth factor), heregulin, angiopoietin, and the like].

Examples of the “cell growth factor receptors” include any receptorscapable of binding to the aforementioned growth factors, including EGFreceptor, heregulin receptor (HER3, etc.), insulin receptor, IGFreceptor-1, IGF receptor-2, FGF receptor-1 or FGF receptor-2, VEGFreceptor, angiopoietin receptor (Tie2 etc.), PDGF receptor, and thelike.

As the “pharmaceutical agents inhibiting the action of cell growthfactors or cell growth factor receptors”, EGF inhibitor, TGFα inhibitor,haregulin inhibitor, insulin inhibitor, IGF inhibitor, FGF inhibitor,KGF inhibitor, CSF inhibitor, EPO inhibitor, IL-2 inhibitor, NGFinhibitor, PDGF inhibitor, TGFβ inhibitor, HGF inhibitor, VEGFinhibitor, angiopoietin inhibitor, EGF receptor inhibitor, HER2inhibitor, HER4 inhibitor, insulin receptor, IGF-1 receptor inhibitor,IGF-2 receptor inhibitor, FGF receptor-1 inhibitor, FGF receptor-2inhibitor, FGF receptor-3 inhibitor, FGF receptor-4 inhibitor, VEGFreceptor inhibitor, Tie-2 inhibitor, PDGF receptor inhibitor, Ablinhibitor, Raf inhibitor, FLT3 inhibitor, c-Kit inhibitor, Srcinhibitor, PKC inhibitor, Trk inhibitor, Ret inhibitor, mTOR inhibitor,Aurora inhibitor, PLK inhibitor, MEK(MEK1/2) inhibitor, MET inhibitor,CDK inhibitor, Akt inhibitor, ERK inhibitor and the like are used. Morespecifically, anti-VEGF antibody (Bevacizumab etc.), anti-HER2 antibody(Trastuzumab, Pertuzumab etc.), anti-EGFR antibody (Cetuximab,Panitumumab, Matuzumab, Nimotuzumab etc.), anti-VEGFR antibody,Imatinib, Erlotinib, Gefitinib, Sorafenib, Sunitinib, Dasatinib,Lapatinib, Vatalanib,4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-[3-(1-pyrrolidinyl)propoxy]quinazoline(AZD-2171), Lestaurtinib, Pazopanib, Canertinib, Tandutinib,3-(4-bromo-2,6-difluorobenzyloxy)-5-[3-[4-(1-pyrrolidinyl)butyl]ureido]isothiazole-4-carboxamide(CP-547632), Axitinib,N-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-(pyridin-4-ylmethylamino)pyridine-3-carboxamide(AMG-706), Nilotinib,6-[4-(4-ethylpiperazin-1-ylmethyl)phenyl]-N-[1(R)-phenylethyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine(AEE-788), Vandetanib, Temsirolimus, Everolimus, Enzastaurin,N-[4-[4-(4-methylpiperazin-1-yl)-6-(3-methyl-1H-pyrazol-5-ylamino)pyrimidin-2-ylsulfanyl]phenyl]cyclopropanecarboxamide(VX-680), phosphoric acid2-[N-[3-[4-[5-[N-(3-fluorophenyl)carbamoylmethyl]-1H-pyrazol-3-ylamino]quinazolin-7-yloxy]propyl]-N-ethylamino]ethylester (AZD-1152),4-[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-ylamino]benzoicacid (MLN-8054),N-[2-methoxy-5-[(E)-2-(2,4,6-trimethoxyphenyl)vinylsulfonylmethyl]phenyl]glycinesodium salt (ON-1910Na),4-[8-cyclopentyl-7(R)-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-ylamino]-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide(BI-2536),5-(4-bromo-2-chlorophenylamino)-4-fluoro-1-methyl-1H-benzimidazole-6-carbohydroxamicacid 2-hydroxyethyl ester (AZD-6244),N-[2(R),3-dihydroxypropoxy]-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)benzamide(PD-0325901) and the like are used.

In addition to the aforementioned drugs, L-asparaginase, aceglatone,procarbazine hydrochloride, protoporphyrin-cobalt complex salt, mercurichematoporphyrin-sodium, topoisomerase I inhibitors (e.g., irinotecan,topotecan, and the like), topoisomerase II inhibitors (e.g., sobuzoxane,and the like), differentiation inducers (e.g., retinoid, vitamin D, andthe like), other angiogenesis inhibitors (e.g., humagillin, sharkextract, COX-2 inhibitor, and the like), α-blockers (e.g., tamsulosinhydrochloride, and the like), bisphosphonic acids (pamidronate,zoledronate, and the like), thalidomide, 5 azacytidine, decitabine,bortezomib, antitumor antibody such as anti-CD20 antibody and the like,toxin labeled antibody and the like can also be used.

By combining the compound of the present invention and a concomitantdrug, a superior effect such as

(1) the dose can be reduced as compared to single administration of thecompound of the present invention or a concomitant drug,

(2) the drug to be combined with the compound of the present inventioncan be selected according to the condition of patients (mild case,severe case and the like),

(3) the period of treatment can be set longer,

(4) a sustained treatment effect can be designed,

(5) a synergistic effect can be afforded by a combined use of thecompound of the present invention and a concomitant drug, and the like,can be achieved.

In the present specification, the compound of the present invention anda concomitant drug used in combination are referred to as the“combination agent of the present invention”.

For use of the combination agent of the present invention, theadministration time of the compound of the present invention and theconcomitant drug is not restricted, and the compound of the presentinvention and the concomitant drug can be administered to anadministration subject simultaneously, or may be administered atdifferent times. The dosage of the concomitant drug may be determinedaccording to the administration amount clinically set, and can beappropriately selected depending on the administration subject,administration route, disease, combination and the like.

Examples of the administration mode of the combined use of the compoundof the present invention and the concomitant drug include the followingmethods:

(1) The compound of the present invention and the concomitant drug aresimultaneously produced to give a single preparation, which is thenadministered. (2) The compound of the present invention and theconcomitant drug are separately produced to give two kinds ofpreparations which are administered simultaneously by the sameadministration route. (3) The compound of the present invention and theconcomitant drug are separately produced to give two kinds ofpreparations which are administered by the same administration route atdifferent times. (4) The compound of the present invention and theconcomitant drug are separately produced to give two kinds ofpreparations which are administered simultaneously by differentadministration routes. (5) The compound of the present invention and theconcomitant drug are separately produced to give two kinds ofpreparations which are administered by different administration routesat different times (for example, the compound of the present inventionand the concomitant drug are administered in this order, or in thereverse order). The dose of the concomitant drug is determined inaccordance with its clinical dose. And the ratio of the compound of thepresent invention and the concomitant drug is determined depending onthe subject, administration route, disease, symptom, combination, andthe like. For example, when the subject is human, the concomitant drugis used in 0.01 to 100 (w/w), relative to the compound of the presentinvention.

The combination agent of the present invention has low toxicity and, forexample, the compound of the present invention and/or theabove-mentioned concomitant drug can be mixed, according to a methodknown per se, with a pharmacologically acceptable carrier to givepharmaceutical compositions, such as tablets (including sugar-coatedtablet, film-coated tablet), powders, granules, capsules (including softcapsule), solutions, injections, suppositories, sustained release agentsand the like, which can be safely administered orally or parenterally(e.g., local, rectum, venous, and the like). An injection can beadministered directly to the lesion by intravenous, intramuscular,subcutaneous or intra-tissue administration.

As a pharmacologically acceptable carrier which may be used forpreparing a preparation of the combination agent of the presentinvention, those similar to the aforementioned pharmacologicallyacceptable carriers, that can be used for the production of thepharmaceutical agent of the present invention, can be mentioned. Wherenecessary, the aforementioned additives that can be used for theproduction of the pharmaceutical agent of the present invention, such aspreservatives, antioxidants, coloring agents, sweetening agents,adsorbents, wetting agents and the like can also be used in appropriateamounts.

The compounding ratio of the compound of the present invention to theconcomitant drug in the combination agent of the present invention canbe appropriately set depending on the administration subject,administration route, diseases and the like.

For example, the content of the compound of the present invention in thecombination agent of the present invention varies depending on thedosage form, and is usually from about 0.01 to 100% by weight,preferably from about 0.1 to 50% by weight, further preferably fromabout 0.5 to 20% by weight, based on the preparation.

The content of the concomitant drug in the combination agent of thepresent invention varies depending on the dosage form, and is usuallyfrom about 0.01 to 90% by weight, preferably from about 0.1 to 50% byweight, further preferably from about 0.5 to 20% by weight, based on thepreparation.

The content of additives in the combination agent of the presentinvention varies depending on the dosage form, and is usually from about1 to 99.99% by weight, preferably from about 10 to 90% by weight, basedon the preparation.

When the compound of the present invention and the concomitant drug areseparately prepared, the same content may be adopted.

These preparations can be produced by a method known per se, which isgenerally employed in the preparation process.

For example, the compound of the present invention and the concomitantdrug can be made into an aqueous injection together with a dispersingagent (e.g., Tween 80 (manufactured by Atlas Powder, US), HCO 60(manufactured by Nikko Chemicals), polyethylene glycol,carboxymethylcellulose, sodium alginate, hydroxypropylmethylcellulose,dextrin and the like), a stabilizer (e.g., ascorbic acid, sodiumpyrosulfite, and the like), a surfactant (e.g., Polysorbate 80, macrogoland the like), a solubilizer (e.g., glycerin, ethanol and the like), abuffer (e.g., phosphoric acid and alkali metal salt thereof, citric acidand alkali metal salt thereof, and the like), an isotonizing agent(e.g., sodium chloride, potassium chloride, mannitol, sorbitol, glucoseand the like), a pH adjusting agent (e.g., hydrochloric acid, sodiumhydroxide and the like), a preservative (e.g., ethyl p-oxybenzoate,benzoic acid, methylparaben, propylparaben, benzyl alcohol and thelike), a dissolving agent (e.g., conc. glycerin, meglumine and thelike), a dissolution aid (e.g., propylene glycol, sucrose and the like),a soothing agent (e.g., glucose, benzyl alcohol and the like), and thelike, or can be dissolved, suspended or emulsified in a vegetable oilsuch as olive oil, sesame oil, cotton seed oil, corn oil and the like ora dissolution aid such as propylene glycol and the like and preparedinto an oily injection, whereby an injection is afforded.

In addition, an excipient (e.g., lactose, sucrose, starch and the like),a disintegrating agent (e.g., starch, calcium carbonate and the like), abinder (e.g., starch, gum Arabic, carboxymethylcellulose,polyvinylpyrrolidone, hydroxypropylcellulose and the like), a lubricant(e.g., talc, magnesium stearate, polyethylene glycol 6000 and the like)and the like may be added to the compound of the present invention orthe concomitant drug according to a method known per se, and the mixturecan be compression-molded, then if desirable, the molded product can becoated by a method known per se for the purpose of masking of taste,enteric property or durability, to give a preparation for oraladministration. As the coating agent, for example,hydroxypropylmethylcellulose, ethylcellulose, hydroxymethylcellulose,hydroxypropylcellulose, polyoxyethylene glycol, Tween 80, Pluronic F68,cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate,hydroxymethylcellulose acetate succinate, Eudoragit (methacrylicacid-acrylic acid copolymer, manufactured by Rohm, Del.), pigment (e.g.,iron oxide red, titanium dioxide, etc.) and the like can be used. Thepreparation for oral administration may be any of an immediate-releasepreparation and a sustained release preparation.

Moreover, the compound of the present invention and the concomitant drugcan be made into an oily or aqueous solid, semisolid or liquidsuppository according to a method known per se, by mixing them with anoily substrate, aqueous substrate or aqueous gel substrate. As theabove-mentioned oily substrate, for example, glycerides of higher fattyacids [e.g., cacao butter, Witepsols (manufactured by Dynamit Nobel,Germany), etc.], glycerides of medium chain fatty acid [e.g., Miglyols(manufactured by Dynamit Nobel, Germany), etc.], or vegetable oils(e.g., sesame oil, soybean oil, cotton seed oil and the like), and thelike are mentioned. Furthermore, as the aqueous substrate, for example,polyethylene glycol, propylene glycol and the like are mentioned, and asthe aqueous gel substrate, for example, natural gums, cellulosederivatives, vinyl polymers, acrylic acid polymers and the like arementioned.

As the above-mentioned sustained release preparation, sustained releasemicrocapsules and the like are mentioned. The sustained releasemicrocapsule can be produced by a method known per se, such as themethod shown in the following [2].

The compound of the present invention is preferably molded into apreparation for oral administration such as a solid preparation (e.g.,powder, granule, tablet, capsule) and the like, or molded into apreparation for rectal administration such as a suppository and thelike. Particularly, a preparation for oral administration is preferable.

The concomitant drug can be made into the above-mentioned drug formdepending on the kind of the drug.

[1] An injection of the compound of the present invention or theconcomitant drug, and preparation thereof, [2] a sustained releasepreparation or immediate-release preparation of the compound of thepresent invention or the concomitant drug, and preparation thereof, [3]a sublingual, buccal or intraoral quick integrating agent of thecompound of the present invention or the concomitant drug, andpreparation thereof, will be specifically described below.

[1] Injection and Preparation Thereof

An injection prepared by dissolving the compound of the presentinvention or the concomitant drug in water is preferable. This injectionmay contain a benzoate and/or salicylate.

The injection is obtained by dissolving the compound of the presentinvention or the concomitant drug, and if desirable, a benzoate and/orsalicylate, in water.

As the above-mentioned salts of benzoic acid and salicylic acid, forexample, salts of alkali metals such as sodium, potassium and the like,salts of alkaline earth metals such as calcium, magnesium and the like,ammonium salts, meglumine salts, salts with organic bases such astromethamol and the like, etc. are mentioned.

The concentration of the compound of the present invention or theconcomitant drug in an injection is from 0.5 to 50 w/v %, preferablyfrom about 3 to 20 w/v %. The concentration of a benzoate and/orsalicylate is from 0.5 to 50 w/v %, preferably from about 3 to 20 w/v %.

The injection of the present invention can be appropriately mixed withan additive conventionally used for injection, such as a stabilizer(e.g., ascorbic acid, sodium pyrosulfite and the like), a surfactant(e.g., Polysorbate 80, macrogol and the like), a solubilizer (e.g.,glycerin, ethanol and the like), a buffer (e.g., phosphoric acid andalkali metal salt thereof, citric acid and alkali metal salt thereof,and the like), an isotonizing agent (e.g., sodium chloride, potassiumchloride and the like), a dispersing agent (e.g.,hydroxypropylmethylcellulose, dextrin), a pH adjusting agent (e.g.,hydrochloric acid, sodium hydroxide and the like), a preservative (e.g.,ethyl p-oxybenzoate, benzoic acid and the like), a dissolving agent(e.g., conc. glycerin, meglumine and the like), a dissolution aid (e.g.,propylene glycol, sucrose and the like), a soothing agent (e.g.,glucose, benzyl alcohol and the like), and the like. These additives aregenerally blended in a proportion usually used for injections.

The pH of an injection is advantageously adjusted to pH 2 to 12,preferably pH 2.5 to 8.0, by addition of a pH adjusting agent.

An injection is obtained by dissolving, in water, the compound of thepresent invention or the concomitant drug and, if desirable, a benzoateand/or a salicylate, and if necessary, the above-mentioned additives.They may be dissolved in any order, and can be appropriately dissolvedin the same manner as in a conventional production method of aninjection.

An aqueous solution for injection may be advantageously heated,alternatively, for example, subjected to filter sterilization, highpressure heat sterilization and the like to give an injection, in thesame manner as for usual injections.

An aqueous solution for injection may be advantageously subjected tohigh pressure heat sterilization at 100° C. to 121° C. for 5 to 30 min.

Furthermore, a preparation conferred with antibacterial property of asolution may also be produced to permit multiple administration inportions.

[2] Sustained Release Preparation or Immediate-Release Preparation, andPreparation Thereof

A sustained release preparation is preferable, which is obtained, ifdesirable, by coating a nucleus containing the compound of the presentinvention or the concomitant drug with a film agent such as awater-insoluble substance, a swellable polymer and the like. Forexample, a sustained release preparation for oral administration of aone-day-one-time administration type is preferable.

As the water-insoluble substance used in a film agent, there are listed,for example, cellulose ethers such as ethylcellulose, butylcellulose andthe like, cellulose esters such as cellulose acetate, cellulosepropionate and the like, polyvinyl esters such as polyvinyl acetate,polyvinyl butyrate and the like, acrylic acid/methacrylic acidcopolymers, methyl methacrylate copolymers, ethoxyethylmethacrylate/cinnamoethyl methacrylate/aminoalkyl methacrylatecopolymers, polyacrylic acid, polymethacrylic acid, methacrylic acidalkylamide copolymers, poly(methyl methacrylate), polymethacrylate,polymethacrylamide, aminoalkyl methacrylate copolymers, poly(methacrylicanhydride), glycidyl methacrylate copolymer, particularly, acrylicacid-based polymers such as Eudoragit (Rohm Pharma) such as EudoragitRS-100, RL-100, RS-30D, RL-30D, RL-PO, RS-PO (ethyl acrylate/methylmethacrylate/trimethyl methacryloyl chloride/ammoniumethyl copolymer),Eudoragit NE-30D (methyl methacrylate/ethyl acrylate copolymer), and thelike, hydrogenated oils such as hydrogenated castor oil (e.g., Lubri wax(Freund Corporation) and the like), waxes such as carnauba wax, glycerinfatty acid ester, paraffin and the like, polyglycerin fatty acid esters,and the like.

As the swellable polymer, polymers having an acidic dissociating groupand showing pH dependent swell are preferable, and polymers having anacidic dissociating group, which manifest small swelling in acidicregions such as in stomach and large swelling in neutral regions such asin small intestine and large intestine, are preferable.

As such a polymer having an acidic dissociating group and showing pHdependent swell, cross-linkable polyacrylic acid copolymers such asCarbomer 934P, 940, 941, 974P, 980, 1342 and the like, polycarbophil,calcium polycarbophil (all of which are manufactured by BF Goodrich),Hiviswako 103, 104, 105, 304 (all are manufactured by Wako Pure ChemicalIndustries, Ltd.), and the like, can be used.

The film agent used in a sustained release preparation may furthercontain a hydrophilic substance.

As the hydrophilic substance, for example, polysaccharides which maycontain a sulfate group such as pullulan, dextrin, alkali metal alginateand the like, polysaccharides having a hydroxyalkyl or carboxyalkyl suchas hydroxypropylcellulose, hydroxypropylmethylcellulose,carboxymethylcellulose sodium and the like, methylcellulose,polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol and thelike can be mentioned.

The content of a water-insoluble substance in the film agent of asustained release preparation is from about 30 to about 90% (w/w),preferably from about 35 to about 80% (w/w), further preferably fromabout 40 to about 75% (w/w), the content of a swellable polymer is fromabout 3 to about 30% (w/w), preferably from about 3 to about 15% (w/w).The film agent may further contain a hydrophilic substance, and in whichcase, the content of a hydrophilic substance in the film agent is about50% (w/w) or less, preferably about 5 to 40% (w/w), further preferablyfrom about 5 to 35% (w/w). This % (w/w) indicates % by weight based on afilm agent composition which is obtained by removing a solvent (e.g.,water, lower alcohols such as methanol, ethanol and the like) from afilm agent solution.

The sustained release preparation is produced by preparing a nucleuscontaining a drugs as exemplified below, then, coating the resultednucleus with a film agent solution prepared by heat-solving awater-insoluble substance, swellable polymer and the like or bydissolving or dispersing it in a solvent.

I. Preparation of Nucleus Containing Drug

The form of nucleus containing a drug to be coated with a film agent(hereinafter, sometimes simply referred to as nucleus) is notparticularly restricted, and preferably, the nucleus is formed intoparticles such as a granule or fine particle.

When the nucleus is composed of granules or fine particles, the averageparticle size thereof is preferably from about 150 to about 2000 μm,further preferably, from about 500 to about 1400 μm.

Preparation of the nucleus can be effected by a usual production method.For example, a suitable excipient, binding agent, disintegrating agent,lubricant, stabilizer and the like are mixed with a drug, and themixture is subjected to a wet extrusion granulating method, fluidizedbed granulating method or the like, to prepare a nucleus.

The content of drugs in a nucleus is from about 0.5 to about 95% (w/w),preferably from about 5.0 to about 80% (w/w), further preferably fromabout 30 to about 70% (w/w).

As the excipient contained in the nucleus, for example, saccharides suchas sucrose, lactose, mannitol, glucose and the like, starch, crystallinecellulose, calcium phosphate, corn starch and the like are used. Amongthem, crystalline cellulose, corn starch are preferable.

As the binding agent, for example, polyvinyl alcohol,hydroxypropylcellulose, polyethylene glycol, polyvinyl pyrrolidone,Pluronic F68, gum Arabic, gelatin, starch and the like are used. As thedisintegrating agent, for example, carboxymethylcellulose calcium(ECG505), croscarmelose sodium (Ac-Di-Sol), crosslinkedpolyvinylpyrrolidone (Crospovidone), low substitutedhydroxypropylcellulose (L-HPC) and the like are used. Among them,hydroxypropylcellulose, polyvinylpyrrolidone, lower substitutedhydroxypropylcellulose are preferable. As the lubricant and coagulationinhibitor, for example, talc, magnesium stearate and inorganic saltsthereof are used, and as the lubricant, polyethylene glycol and the likeare used. As the stabilizer, acids such as tartaric acid, citric acid,succinic acid, fumaric acid, maleic acid and the like, are used.

A nucleus can also be prepared by, in addition to the above-mentioned,for example, a rolling granulation method in which a drug or a mixtureof a drug with an excipient, lubricant and the like is added portionwiseonto an inert carrier particle which is the core of the nucleus whilespraying a binder dissolved in a suitable solvent such as water, loweralcohol (e.g., methanol, ethanol and the like) and the like, a pancoating method, a fluidized bed coating method or a melt granulatingmethod. As the inert carrier particle, for example, those made ofsucrose, lactose, starch, crystalline cellulose or waxes can be used,and the average particle size thereof is preferably from about 100 μm toabout 1500 μm.

For separating a drug contained in a nucleus and a film agent, thesurface of the nucleus may be coated with a protective agent. As theprotective agent, for example, the above-mentioned hydrophilicsubstances, water-insoluble substances and the like are used. As theprotective agent, preferably polyethylene glycol, and polysaccharideshaving a hydroxyalkyl or carboxyalkyl are used, more preferably,hydroxypropylmethylcellulose and hydroxypropylcellulose are used. Theprotective agent may contain, as stabilizer, acids such as tartaricacid, citric acid, succinic acid, fumaric acid, maleic acid and thelike, and lubricants such as talc and the like. When the protectiveagent is used, the coating amount is from about 1 to about 15% (w/w),preferably from about 1 to about 10% (w/w), further preferably fromabout 2 to about 8% (w/w), based on the nucleus.

The protective agent can be coated by a usual coating method, andspecifically, the protective agent can be coated by spray-coating thenucleus, for example, by a fluidized bed coating method, pan coatingmethod and the like.

II. Coating of Nucleus with Film Agent

A nucleus obtained in the above-mentioned step I is coated with a filmagent solution obtained by heat-solving the above-mentionedwater-insoluble substance and pH-dependent swellable polymer, and ahydrophilic substance, or by dissolving or dispersing them in a solvent,to give a sustained release preparation.

As the method for coating a nucleus with a film agent solution, forexample, a spray coating method and the like are listed.

The composition ratio of a water-insoluble substance, swellable polymeror hydrophilic substance in a film agent solution is appropriatelyselected so that the contents of these components in a coated film arethe above-mentioned contents, respectively.

The coating amount of a film agent is from about 1 to about 90% (w/w),preferably from about 5 to about 50% (w/w), further preferably fromabout 5 to about 35% (w/w), based on a nucleus (not including coatingamount of protective agent).

As the solvent in a film agent solution, water or an organic solvent canbe used alone or in admixture thereof. In the case of use in admixture,the mixing ratio of water to an organic solvent (water/organic solvent:by weight) can be varied in the range from 1 to 100%, and preferablyfrom 1 to about 30%. The organic solvent is not particularly restrictedproviding it dissolves a water-insoluble substance, and for example,lower alcohols such as methyl alcohol, ethyl alcohol, isopropyl alcohol,n-butyl alcohol and the like, lower alkanone such as acetone and thelike, acetonitrile, chloroform, methylene chloride and the like areused. Among them, lower alcohols are preferable, and ethyl alcohol andisopropyl alcohol are particularly preferable. Water, and a mixture ofwater with an organic solvent are preferably used as a solvent for afilm agent. In this case, if necessary, an acid such as tartaric acid,citric acid, succinic acid, fumaric acid, maleic acid and the like mayalso be added into a film agent solution for stabilizing the film agentsolution.

An operation of coating by spray coating can be effected by a usualcoating method, and specifically, it can be effected by spray-coating afilm agent solution onto a nucleus by a fluidized bed coating method,pan coating method and the like. In this case, if necessary, talc,titanium oxide, magnesium stearate, calcium stearate, light anhydroussilicic acid and the like may also be added as a lubricant, and glycerinfatty acid ester, hydrogenated castor oil, triethyl citrate, cetylalcohol, stearyl alcohol and the like may also be added as aplasticizer.

After coating with a film agent, if necessary, an antistatic agent suchas talc and the like may be mixed.

The immediate-release preparation may be liquid (solution, suspension,emulsion and the like) or solid (particle, pill, tablet and the like).As the immediate-release preparation, oral agents and parenteral agentssuch as an injection and the like are used, and oral agents arepreferable.

The immediate-release preparation, usually, may contain, in addition toan active component drug, also carriers, additives and excipientsconventionally used in the production field (hereinafter, sometimesabbreviated as excipient). The excipient used is not particularlyrestricted providing it is an excipient ordinarily used as a preparationexcipient. For example, as the excipient for an oral solid preparation,lactose, starch, corn starch, crystalline cellulose (Avicel PH101,manufactured by Asahi Kasei Corporation, and the like), powder sugar,granulated sugar, mannitol, light anhydrous silicic acid, magnesiumcarbonate, calcium carbonate, L-cysteine and the like are listed, andpreferably, corn starch and mannitol and the like are listed. Theseexcipients can be used alone or in combination of two or more. Thecontent of the excipient is, for example, from about 4.5 to about 99.4w/w %, preferably from about 20 to about 98.5 w/w %, further preferablyfrom about 30 to about 9.7 w/w %, based on the total amount of theimmediate-release preparation.

The content of a drug in the immediate-release preparation can beappropriately selected in the range from about 0.5 to about 95%,preferably from about 1 to about 60% based on the total amount of theimmediate-release preparation.

When the immediate-release preparation is an oral solid preparation, itusually contains, in addition to the above-mentioned components, also anintegrating agent. As this integrating agent, for example,carboxymethylcellulose calcium (ECG-505, manufactured by GotokuYakuhin), croscarmelose sodium (for example, Actisol, manufactured byAsahi Kasei Corporation), crospovidone (for example, Kollidon CL,manufactured by BASF), low substituted hydroxypropylcellulose(manufactured by Shin-Etsu Chemical Co., Ltd.), carboxymethylstarch(manufactured by Matsutani Kagaku K.K.), carboxymethylstarch sodium(Exprotab, manufactured by Kimura Sangyo), partially pregelatinizedstarch (PCS, manufactured by Asahi Kasei Corporation), and the like areused, and for example, those which disintegrate a granule by adsorbingwater in contact with water, causing swelling, or making a channelbetween an effective ingredient constituting the nucleus and anexcipient, can be used. These disintegrating agents can be used alone orin combination of two or more. The amount of the disintegrating agentused is appropriately selected depending on the kind and blending amountof a drug used, design of releasing property, and the like, and forexample, from about 0.05 to about 30 w/w %, preferably from about 0.5 toabout 15 w/w %, based on the total amount of the quick releasing agent.

When the immediate-release preparation is an oral solid preparation, itmay further contain, in addition to the above-mentioned composition, ifdesired, additives conventional in solid preparations. As such anadditive, there are used, for example, a binder (e.g., sucrose, gelatin,gum Arabic powder, methylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose, carboxymethylcellulose,polyvinylpyrrolidone, pullulan, dextrin and the like), a lubricant(e.g., polyethylene glycol, magnesium stearate, talc, light anhydroussilicic acid (for example, Aerosil (Nippon Aerosil)), a surfactant(e.g., anionic surfactants such as sodium alkylsulfate and the like,nonionic surfactants such as polyoxyethylene fatty acid ester andpolyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oilderivatives and the like), a coloring agent (e.g., tar coloring matter,caramel, iron oxide red, titanium oxide, riboflavins), if necessary, anappetizing agent (e.g., sweetening agent, flavoring agent and the like),an adsorbent, preservative, wetting agent, antistatic agent, and thelike. Further, as the stabilizer, an organic acid such as tartaric acid,citric acid, succinic acid, fumaric acid and the like may also be added.

As the above-mentioned binder, hydroxypropylcellulose, polyethyleneglycol and polyvinylpyrrolidone and the like are preferably used.

The immediate-release preparation can be prepared by, based on a usualtechnology of producing preparations, mixing the above-mentionedcomponents, and if necessary, further kneading the mixture, and moldingit. The above-mentioned mixing is conducted by generally used methods,for example, mixing, kneading and the like. Specifically, when aimmediate-release preparation is formed, for example, into a particle,it can be prepared, according to the same means as in theabove-mentioned method for preparing a nucleus of a sustained releasepreparation, by mixing the components using a vertical granulator,universal kneader (manufactured by Hata Tekkosho), fluidized bedgranulator FD-5S (manufactured by Powrex Corporation), and the like, andthen, granulating the mixture by a wet extrusion granulation method,fluidized bed granulation method and the like.

Thus obtained immediate-release preparation and sustained releasepreparation may be themselves made into products or made into productsappropriately together with preparation excipients and the like,separately, by an ordinary method, then, may be administeredsimultaneously or may be administered in combination at anyadministration interval, or they may be themselves made into one oralpreparation (e.g., granule, fine particle, tablet, capsule and the like)or made into one oral preparation appropriately together withpreparation excipients and the like. It may also be permissible thatthey are made into granules or fine particles, and filled in the samecapsule to be used as a preparation for oral administration.

[3] Sublingual, Buccal or Intraoral Quick Disintegrating Agent andPreparation Thereof

Sublingual, buccal or intraoral quick disintegrating agents may be asolid preparation such as tablet and the like, or may be an oral mucosamembrane patch (film).

As the sublingual, buccal or intraoral quick disintegrating agent, apreparation containing the compound of the present invention or theconcomitant drug and an excipient is preferable. It may contain alsoauxiliary agents such as a lubricant, isotonizing agent, hydrophiliccarrier, water-dispersible polymer, stabilizer and the like. Further,for easy absorption and increased in vivo use efficiency, β-cyclodextrinor β-cyclodextrin derivatives (e.g., hydroxypropyl-β-cyclodextrin andthe like) and the like may also be contained.

As the above-mentioned excipient, lactose, sucrose, D-mannitol, starch,crystalline cellulose, light anhydrous silicic acid and the like arelisted. As the lubricant, magnesium stearate, calcium stearate, talc,colloidal silica and the like are listed, and particularly, magnesiumstearate and colloidal silica are preferable. As the isotonizing agent,sodium chloride, glucose, fructose, mannitol, sorbitol, lactose,saccharose, glycerin, urea and the like are listed, and particularly,mannitol is preferable. As the hydrophilic carrier, swellablehydrophilic carriers such as crystalline cellulose, ethylcellulose,crosslinkable polyvinylpyrrolidone, light anhydrous silicic acid,silicic acid, dicalcium phosphate, calcium carbonate and the like arelisted, and particularly, crystalline cellulose (e.g., microcrystallinecellulose and the like) is preferable. As the water-dispersible polymer,gums (e.g., gum tragacanth, acacia gum, cyamoposis gum), alginates(e.g., sodium alginate), cellulose derivatives (e.g., methylcellulose,carboxymethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose), gelatin, water-soluble starch,polyacrylic acids (e.g., Carbomer), polymethacylic acid, polyvinylalcohol, polyethylene glycol, polyvinylpyrrolidone, polycarbophil,ascorbic acid, palmitates and the like are listed, andhydroxypropylmethylcellulose, polyacrylic acid, alginates, gelatin,carboxymethylcellulose, polyvinylpyrrolidone, polyethylene glycol andthe like are preferable. Particularly, hydroxypropylmethylcellulose ispreferable. As the stabilizer, cysteine, thiosorbitol, tartaric acid,citric acid, sodium carbonate, ascorbic acid, glycine, sodium sulfiteand the like are listed, and particularly, citric acid and ascorbic acidare preferable.

The sublingual, buccal or intraoral quick disintegrating agent can beproduced by mixing the compound of the present invention or theconcomitant drug and an excipient by a method known per se. Further, ifdesired, auxiliary agents such as a lubricant, isotonizing agent,hydrophilic carrier, water-dispersible polymer, stabilizer, coloringagent, sweetening agent, preservative and the like may be mixed. Thesublingual, buccal or intraoral quick disintegrating agent is obtainedby mixing the above-mentioned components simultaneously or at a timeinterval, then subjecting the mixture to tablet-making molding underpressure. For obtaining suitable hardness, it may also be permissiblethat the materials are moistened by using a solvent such as water,alcohol and the like if desired before and after the tablet makingprocess, and after the molding, the materials are dried, to obtain aproduct.

In the case of molding into a mucosa membrane patch (film), the compoundof the present invention or the concomitant drug and the above-mentionedwater-dispersible polymer (preferably, hydroxypropylcellulose,hydroxypropylmethylcellulose), excipient and the like are dissolved in asolvent such as water and the like, and the resulted solution is cast togive a film. Further, additives such as a plasticizer, stabilizer,antioxidant, preservative, coloring agent, buffer, sweetening agent andthe like may also be added. For imparting suitable elasticity to thefilm, glycols such as polyethylene glycol, propylene glycol and the likemay be contained, or for enhancing adhesion of the film to an intraoralmucosa membrane lining, a bio-adhesive polymer (e.g., polycarbophil,carbopol) may also be contained. In the casting, a solution is poured onthe non-adhesive surface, spread to uniform thickness (preferably, about10 to 1000 micron) by an application tool such as a doctor blade and thelike, then, the solution is dried to form a film. It may be advantageousthat thus formed film is dried at room temperature or under heat, andcut into a desired area.

As the preferable intraoral quick disintegrating agent, there are listedsolid quick scattering dose agents composed of a network body comprisingthe compound of the present invention or the concomitant drug, and awater-soluble or water-diffusible carrier which is inert to the compoundof the present invention or concomitant drug, are listed. This networkbody is obtained by sublimating a solvent from the solid compositionconstituted of a solution prepared by dissolving the compound of thepresent invention or the concomitant drug in a suitable solvent.

It is preferable that the composition of an intraoral quickdisintegrating agent contains a matrix forming agent and a secondarycomponent, in addition to the compound of the present invention or theconcomitant drug.

Examples of the matrix forming agent include gelatins, dextrins, animalproteins or vegetable proteins such as soybean, wheat and psyllium seedprotein and the like; rubber substances such as gum Arabic, guar gum,agar, xanthane gum and the like; polysaccharides; alginic acids;carboxymethylcelluloses; carageenans; dextrans; pectines; syntheticpolymers such as polyvinylpyrrolidone and the like; substances derivedfrom a gelatin-gum Arabic complex, and the like. Further, saccharidessuch as mannitol, dextrose, lactose, galactose, trehalose and the like;cyclic saccharides such as cyclodextrin and the like; inorganic saltssuch as sodium phosphate, sodium chloride and aluminum silicate and thelike; amino acids having 2 to 12 carbon atoms such as glycine,L-alanine, L-aspartic acid, L-glutamic acid, L-hydroxyproline,L-isoleucine, L-leucine, L-phenylalanine and the like, are contained.

One or more of the matrix forming agents can be introduced in a solutionor suspension before solidification. Such as matrix forming agent may bepresent in addition to a surfactant, or may be present while asurfactant being excluded. The matrix forming agents aid to maintain thecompound of the present invention or the concomitant drug in thesolution or suspension in diffused condition, in addition to formationof the matrix.

The composition may contain secondary components such as a preservative,antioxidant, surfactant, thickening agent, coloring agent, pHcontrolling agent, flavoring agent, sweetening agent, food taste maskingagent and the like. As the suitable coloring agent, there are listedred, black and yellow iron oxides, and FD & C dyes such as FD & C Blue2, FD & C Red 40 and the like manufactured by Ellis and Everard.Examples of the suitable flavoring agent include mint, raspberry,licorice, orange, lemon, grapefruit, caramel, vanilla, cherry, grapeflavor and combinations thereof. Examples of the suitable pH controllingagent include citric acid, tartaric acid, phosphoric acid, hydrochloricacid and maleic acid. Examples of the suitable sweetening agent includeaspartame, acesulfame K and thaumatin and the like. Examples of thesuitable food taste masking agent include sodium bicarbonate, ionexchange resin, cyclodextrin-inclusion compounds, adsorbent substancesand microcapsulated apomorphine.

The preparation contains the compound of the present invention or theconcomitant drug in an amount usually from about 0.1 to about 50% byweight, preferably from about 0.1 to about 30% by weight, and preferableare preparations (such as the above-mentioned sublingual agent, buccaland the like) which can dissolve 90% or more of the compound of thepresent invention or the concomitant drug (into water) within the timerange of about 1 to about 60 min, preferably of about 1 to about 15 min,more preferably of about 2 to about 5 min, and intraoral quickdisintegrating preparations which are disintegrated within the range of1 to 60 sec, preferably of 1 to 30 sec, further preferably of 1 to 10sec, after placed in an oral cavity.

The content of the above-mentioned excipient in the whole preparation isfrom about 10 to about 99% by weight, preferably from about 30 to about90% by weight. The content of β-cyclodextrin or β-cyclodextrinderivative in the whole preparation is from 0 to about 30% by weight.The content of the lubricant in the whole preparation is from about 0.01to about 10% by weight, preferably from about 1 to about 5% by weight.The content of the isotonizing agent in the whole preparation is fromabout 0.1 to about 90% by weight, preferably, from about 10 to about 70%by weight. The content of the hydrophilic carrier in the wholepreparation is from about 0.1 to about 50% by weight, preferably, fromabout 10 to about 30% by weight. The content of the water-dispersiblepolymer in the whole preparation is from about 0.1 to about 30% byweight, preferably, from about 10 to about 25% by weight. The content ofthe stabilizer in the whole preparation is from about 0.1 to about 10%by weight, preferably, from about 1 to 5% by weight. The above-mentionedpreparation may further contain additives such as a coloring agent,sweetening agent, preservative and the like, if necessary.

The dosage of a combination agent of the present invention differsdepending on the kind of a compound of the present invention, age, bodyweight, condition, drug form, administration method, administrationperiod and the like, and for example, for one cancer patient (adult,body weight: about 60 kg), the combination agent is administeredintravenously, at a dose of about 0.01 to about 1000 mg/kg/day,preferably about 0.01 to about 100 mg/kg/day, more preferably about 0.1to about 100 mg/kg/day, particularly about 0.1 to about 50 mg/kg/day,especially about 1.5 to about 30 mg/kg/day, in terms of the compound ofthe present invention or the concomitant drug, respectively, once orseveral times in division a day. Of course, since the dose as describedabove varies depending on various conditions, amounts smaller than theabove-mentioned dosage may sometimes be sufficient, further, amountsover that range sometimes have to be administered.

The amount of the concomitant drug can be set at any value unless sideeffects are problematical. The daily dosage in terms of the concomitantdrug differs depending on the severity of the symptom, age, sex, bodyweight, sensitivity difference of the subject, administration period,interval, and nature, pharmacy, kind of the pharmaceutical preparation,kind of effective ingredient, and the like, and not particularlyrestricted, and the amount of a drug is, in the case of oraladministration for example, usually from about 0.001 to 2000 mg,preferably from about 0.01 to 500 mg, further preferably from about 0.1to 100 mg, per 1 kg of a mammal and this is usually administered once to4-times in division a day.

In administration of a combination agent of the present invention, thecompound of the present invention may be administered afteradministration of the concomitant drug or the concomitant drug may beadministered after administration of the compound of the presentinvention, though they may be administered simultaneously. Whenadministered at a time interval, the interval differs depending on theeffective ingredient to be administered, drug form and administrationmethod, and for example, when the concomitant drug is administeredfirst, a method in which the compound of the present invention isadministered within time range of from 1 min to 3 days, preferably from10 min to 1 day, more preferably from 15 min to 1 hr afteradministration of the concomitant drug is exemplified. When the compoundof the present invention is administered first, a method in which theconcomitant drug is administered within time range of from 1 min to 1day, preferably from 10 min to 6 hrs, more preferably from 15 min to 1hr after administration of the compound of the present invention isexemplified.

In a preferable administration method, for example, the concomitant drugwhich has been molded into an oral administration preparation isadministered orally at a daily dose of about 0.001 to 200 mg/kg, andabout 15 min later, the compound of the present invention which has beenmolded into an oral administration preparation is administered orally ata daily dose of about 0.005 to 100 mg/kg.

Furthermore, the compound of the present invention or the combinationagent of the present invention can be used concurrently with a non-drugtherapy. To be precise, the compound of the present invention and thecombination agent of the present invention can be combined with anon-drug therapy such as (1) surgery, (2) hypertensive chemotherapyusing angiotensin II etc., (3) gene therapy, (4) thermotherapy, (5)cryotherapy, (6) laser cauterization, (7) radiotherapy, and the like.

For example, by using the compound of the present invention or thecombination agent of the present invention before or after an surgeryand the like, or before or after a combined treatment of two or threekinds thereof, effects such as prevention of emergence of resistance,prolongation of Disease-Free Survival, suppression of cancer metastasisor recurrence, prolongation of life and the like can be afforded.

In addition, it is possible to combine a treatment with the compound ofthe present invention or the combination agent of the present inventionwith a supportive therapy [(i) administration of antibiotic (e.g.,β-lactam type such as pansporin and the like, macrolide type such asclarithromycin and the like etc.) for the complication with variousinfectious diseases, (ii) administration of total parenteral nutrition,amino acid preparation or general vitamin preparation for theimprovement of malnutrition, (iii) administration of morphine for painmitigation, (iv) administration of a pharmaceutical agent for improvingside effects such as nausea, vomiting, anorexia, diarrhea, leucopenia,thrombocytopenia, decreased hemoglobin concentration, hair loss,hepatopathy, renopathy, DIC, fever and the like and (v) administrationof a pharmaceutical agent for suppressing multiple drug resistance ofcancer and the like].

Preferably, the compound of the present invention or the combinationagent of the present invention is administered orally (includingsustained-release preparations), intravenously (including boluses,infusions and clathrates), subcutaneously and intramuscularly (includingboluses, infusions and sustained-release preparations), transdermally,intratumorally or proximally before or after the above-describedtreatment is conducted.

As a period for administering the compound of the present invention orthe combination agent of the present invention before the surgery, etc.,for example, it can be administrated 1-time about 30 min to 24 hrsbefore the surgery, etc., or in 1 to 3 cycles about 3 months to 6 monthsbefore the surgery, etc. In this way, the surgery, etc. can be conductedeasily because, for example, a cancer tissue would be reduced byadministering the compound of the present invention or the combinationagent of the present invention before the surgery, and the like.

As a period for administering the compound of the present invention orthe combination agent of the present invention after the surgery, etc.,for example, it can be administrated repeatedly per a few weeks to 3months, about 30 min to 24 hrs after the surgery, and the like. In thisway, it enhances the effect of the surgery, etc. by administering thecompound of the present invention or the combination agent of thepresent invention after the surgery, and the like.

EXAMPLES

The present invention is specifically explained in the following by wayof Reference Examples, Examples, Formulation Examples, ExperimentalExamples and Test Examples, which are not to be construed as limitative.

The LC/MS analysis in the Examples was performed under the followingconditions.

measurement tool: Waters Corporation ZQ

column: manufactured by Shiseido Co., Ltd. CAPCELL PAK C18 UG120 S-3 3μm, 35×1.5 mm

solvent: SOLUTION A; 5 mM aqueous ammonium acetate/acetonitrile=98/2

-   -   SOLUTION B; 100 mM aqueous ammonium acetate/acetonitrile=5/95        gradient cycle: 0.00 min (SOLUTION A/SOLUTION B=100/0), 2.00 min        (SOLUTION A/SOLUTION B=0/100), 3.00 min (SOLUTION A/SOLUTION        B=0/100), 3.01 min (SOLUTION A/SOLUTION B=100/0), 3.80 min        (SOLUTION A/SOLUTION B=100/0)        flow rate: 0.5 mL/min, Column temperature was room temperature        with no temperature control.        ionization method: Electron Spray Ionization, ESI positive and        negative ion peaks were detected.        The percentage of the peak area detected at UV: 220 nm of the        resultant product peak was taken as the purity of the compound.

In the Examples, preparative HPLC was performed as in the following.

Preparative HPLC tools: Gilson, Inc. High-Throughput purification system

column: YMC Combiprep Hydrosphere C18 S-5 5 μm, 12 nM. 50×20 mm

solvent: SOLUTION A; water

-   -   SOLUTION B; acetonitrile        gradient cycle: 0.00 min (SOLUTION A/SOLUTION B=98/2), 1.10 min        (SOLUTION A/SOLUTION B=98/2), 5.00 min (SOLUTION A/SOLUTION        B=0/100), 6.40 min (SOLUTION A/SOLUTION B=0/100), 6.50 min        (SOLUTION A/SOLUTION B=2/98), 6.52 min (SOLUTION A/SOLUTION        B=2/98)        flow rate: 25 mL/min, detection method: UV 220 nm

Unless otherwise specified, the elution by column chromatography wasperformed under observation by TLC (thin layer chromatography) inReference Examples and Examples. For TLC observation, 60F254manufactured by Merck, or NH TLC plate manufactured by Fuji SilysiaChemical Ltd. was used as a TLC plate, and the solvent used as anelution solvent in column chromatography was used as a developingsolvent. For detection, moreover, a UV detector was employed. As thesilica gel for column chromatography, silica gel 60 (70-230 mesh)manufactured by Merck, NH silica gel (100-200 mesh) manufactured by FujiSilysia Chemical Ltd. and the like were used. The room temperaturegenerally means from about 10° C. to 35° C. For drying the extract,anhydrous sodium sulfate or anhydrous magnesium sulfate was used.

In Formulation Examples, the Japanese Pharmacopoeia 14th Edition orJapanese Pharmaceutical Excipients 2003 compatible products are used asthe preparation additives (e.g., lactose, cornstarch, magnesiumstearate, microcrystalline cellulose). Abbreviations in the Examples andReference Examples mean the following.

LC: liquid chromatography

MS: mass spectrometry

ESI: electrospray ionization

FAB: fast atomic beam

M: molecular ion peak

NMR: nuclear magnetic resonance spectra

Hz: hertz

J: coupling constant

m: multiplet

q: quartet

t: triplet

d: doublet

s: singlet

br: broad

dt: double triplet

brs: broad singlet

wt %: weight percent

DMSO: dimethyl sulfoxide

Reference Example 1 Production of tert-butyl (chloroacetyl)carbamate

To a suspension of 2-chloroacetamide (25 g, 267 mmol) in1,2-dichloroethane (125 mL) was added dropwise oxalyl chloride (28 mL,321 mmol) at 0° C. After heating under reflux for 3 hr, the mixture wascooled to 0° C., tert-butyl alcohol/1,2-dichloroethane (75 mL, 1/1) wasadded to the mixture, and the mixture was stirred for 20 min. Saturatedaqueous sodium hydrogencarbonate solution was added to the reactionmixture, and the mixture was extracted with 1,2-dichloroethane. Afterwashing with saturated aqueous sodium hydrogencarbonate solution andwater, the extract was dried over anhydrous magnesium sulfate andfiltrated. The solvent was evaporated under reduced pressure, and theresidue was recrystallized from cyclohexane to give the title compound(25.6 g, 49%) as white crystals.

¹H-NMR (CDCl₃, 300 MHz) δ 1.58 (9H, s), 4.46 (2H, s), 7.59 (1H, br).

Reference Example 2 Production of tert-butyl(6-iodoimidazo[1,2-b]pyridazin-2-yl)carbamate

To a solution of 3-amino-6-iodopyridazine (10.0 g, 45.2 mmol) inN,N-dimethylacetamide (100 mL) were added tert-butyl(chloroacetyl)carbamate (14.0 g, 72.4 mmol) and disodiumhydrogenphosphate (16.1 g, 113 mmol), and the mixture was stirred at120° C. for 3 hr. After cooling the mixture to room temperature, water(400 mL) was added to the mixture, and the precipitated crystals werefiltrated, and washed with acetonitrile and petroleum ether to give thetitle compound (10.2 g, 63%) as a green powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.49 (9H, s), 7.45 (1H, d, J=9.5 Hz), 7.69(1H, d, J=9.5 Hz), 8.01 (1H, brs), 10.20 (1H, brs).

Reference Example 3 Production of ethyl(6-iodoimidazo[1,2-b]pyridazin-2-yl)carbamate

To a solution of 3-amino-6-iodopyridazine (27.0 g, 122 mmol) inN,N-dimethylacetamide (270 mL) were added ethyl (chloroacetyl)carbamate(32.4 g, 195 mmol) and disodium hydrogenphosphate (43.4 g, 305 mmol),and the mixture was stirred at 110° C. for 3 hr. After cooling themixture to room temperature, water (810 mL) was added, and theprecipitated crystals were filtrated, and washed with acetonitrile andether to give the title compound (33.0 g, 81%) as a dark brown powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.26 (3H, t, J=7.1 Hz), 4.17 (2H, q, J=7.1Hz), 7.47 (1H, d, J=9.2 Hz), 7.70 (1H, d, J=9.2 Hz), 8.06 (1H, s), 10.51(1H, brs).

Reference Example 4-1 Production of6-iodoimidazo[1,2-b]pyridazin-2-amine

To a suspension of tert-butyl(6-iodoimidazo[1,2-b]pyridazin-2-yl)carbamate (10.2 g, 28.3 mmol) inethyl acetate (50 mL) was added 4N hydrochloric acid/ethyl acetate (75mL), and the mixture was stirred at room temperature for 4 hr. Diethylether (200 mL) was added to the reaction mixture, and the precipitatewas filtrated. After washing with saturated aqueous sodiumhydrogencarbonate solution, the filtrate was washed with water,acetonitrile and diethyl ether to give the title compound (4.9 g, 67%)as a green powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 5.61 (2H, s), 7.22 (1H, d, J=8.7 Hz), 7.36(1H, s), 7.39 (1H, d, J=8.7 Hz).

Reference Example 4-2 Production of6-iodoimidazo[1,2-b]pyridazin-2-amine

To barium hydroxide octahydrate (14.5 g, 46.1 mmol) was added water (240mL), and the mixture was stirred at 80° C. for 15 min. A solution ofethyl (6-iodoimidazo[1,2-b]pyridazin-2-yl)carbamate (10.2 g, 30.7 mmol)in N-methylpyrrolidone (80 mL) was added to the mixture, and the mixturewas stirred at 120° C. for 8 hr. After cooling the mixture to roomtemperature, water (480 mL) was added to the mixture, and the mixturewas stirred for 1 hr. The mixture was extracted twice with ethylacetate/tetrahydrofuran, washed with saturated brine, dried overanhydrous magnesium sulfate, and filtrated. The solvent was evaporatedunder reduced pressure, diisopropyl ether was added to the residue, andthe precipitated crystals were collected by filtration to give the titlecompound (6.1 g, 76%) as a brown powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 5.61 (2H, s), 7.22 (1H, d, J=8.7 Hz), 7.36(1H, s), 7.39 (1H, d, J=8.7 Hz).

Reference Example 5 Production ofN-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide

To a solution (10 mL) of 6-iodoimidazo[1,2-b]pyridazin-2-amine (1.0 g,3.85 mmol) in N,N-dimethylacetamide was added cyclopropylcarbonylchloride (0.38 mL, 4.23 mmol), and the mixture was stirred at roomtemperature for 4 hr. Water was added to the reaction mixture, and themixture was extracted with ethyl acetate/tetrahydrofuran. The extractwas washed with saturated brine, dried over anhydrous magnesium sulfate,and filtrated. The solvent was evaporated under reduced pressure, andthe residue was washed with hexane/ethyl acetate (4/1) to give the titlecompound (1.01 g, 80%) as a dark brown powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.82-0.86 (4H, m), 1.90-2.00 (1H, m), 7.49(1H, d, J=9.3 Hz), 7.73 (1H, d, J=9.3 Hz), 8.23 (1H, s), 11.20 (1H, s).

Reference Example 7 Production of3-methyl-1-(2,2,2-trifluoroethyl)-1H-pyrazole-5-carboxylic acid

To a suspension of sodium hydride (1.62 g, 40.4 mmol) inN,N-dimethylformamide (250 mL) was added dropwise a solution of ethyl3-methyl-1H-pyrazole-5-carboxylate (5660 mg, 36.8 mmol) inN,N-dimethylformamide (50 mL) over 10 min under ice-cooling. After thecompletion of the dropwise addition, the reaction mixture was stirred at0° C. for 10 min and at room temperature for 40 min. To the mixture wasadded 2,2,2-trifluoroethyl trifluoromethanesulfonate (9.87 g, 40.4mmol), and the mixture was stirred at room temperature for 3 hr. Underice-cooling, 1N hydrochloric acid (36 mL) was added to the mixture, andthe solvent was evaporated under reduced pressure. Ethylacetate/tetrahydrofuran and saturated aqueous sodium hydrogencarbonatesolution were added to the residue, and the aqueous layer was extractedthree times with ethyl acetate/tetrahydrofuran. Combined organic layerwas washed with saturated brine, dried over anhydrous sodium sulfate,and filtrated. The solvent was evaporated under reduced pressure, andthe residue was purified by silica gel column chromatography (ethylacetate/hexane=5/95→60/40), and recrystallized from ethyl acetate/hexaneto give ethyl3-methyl-1-(2,2,2-trifluoroethyl)-1H-pyrazole-5-carboxylate (1.98 g,23%) as white crystals.

To a solution of ethyl3-methyl-1-(2,2,2-trifluoroethyl)-1H-pyrazole-5-carboxylate (1.74 g,7.36 mmol) in tetrahydrofuran (5.0 mL) was added 8N sodium hydroxide(4.6 mL), and the mixture was stirred at room temperature for 2 hr. 6Nhydrochloric acid (6.0 mL) was added to the mixture (pH=3), and theaqueous layer was extracted three times with ethylacetate/tetrahydrofuran. Combined organic layer was washed withsaturated brine, dried over anhydrous sodium sulfate, and filtrated. Thesolvent was evaporated under reduced pressure, and the residue wasfiltrated, and washed with ethyl acetate/hexane to give the titlecompound (1.28 g, 84%) as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 2.19 (3H, s), 5.36 (2H, q, J=9.0 Hz), 6.76(1H, s), 13.66 (1H, brs).

Reference Example 8 Production of ethyl6-iodoimidazo[1,2-b]pyridazine-2-carboxylate

Using 3-amino-6-iodopyridazine (2.0 g, 9.05 mmol), N,N-dimethylacetamide(20 mL), ethyl 3-bromo-2-oxopropanate (1.82 mL, 14.5 mmol) and disodiumhydrogenphosphate (3.21 g, 22.6 mmol), and in the same manner as inReference Example 3, the title compound (1.2 g, 44%) was obtained as agreen powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.33 (3H, t, J=7.1 Hz), 4.33 (2H, q, J=7.1Hz), 7.65 (1H, d, J=9.5 Hz), 7.96 (1H, d, J=9.5 Hz), 8.88 (1H, s).

Reference Example 9 Production of6-iodo-N-methylimidazo[1,2-b]pyridazine-2-carboxamide

To a suspension of ethyl 6-iodoimidazo[1,2-b]pyridazine-2-carboxylate(4.5 g, 14.8 mmol) in methanol (13.5 mL) was added dropwise a solutionof methylamine/tetrahydrofuran (2 mol/L, 37.1 mL, 74.2 mmol), and themixture was stirred at room temperature for 96 hr. The solvent wasevaporated under reduced pressure, and the residue was washed with ethylacetate, saturated brine and water to give the title compound (3.2 g,71%) as a dark brown powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 2.79 (3H, d, J=4.8 Hz), 7.62 (1H, d, J=9.6Hz), 7.90 (1H, d, J=9.6 Hz), 8.46-8.55 (1H, m), 8.65 (1H, s).

Reference Example 10 Production ofN-(6-iodoimidazo[1,2-b]pyridazin-2-yl)-2-methoxyacetamide

Using 6-iodoimidazo[1,2-b]pyridazin-2-amine (1.0 g, 3.85 mmol),N,N-dimethylacetamide (10 mL) and methoxyacetyl chloride (0.46 g, 4.23mmol) as starting materials and in the same manner as in ReferenceExample 5, the title compound (1.01 g, 79%) was obtained as a dark brownpowder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 3.36 (3H, s), 4.09 (2H, s), 7.51 (1H, d,J=9.6 Hz), 7.75 (1H, d, J=9.6 Hz), 8.30 (1H, s), 10.73 (1H, s).

Reference Example 11 Production ofN-(6-iodoimidazo[1,2-b]pyridazin-2-yl)-2-methylpropanamide

Using 6-iodoimidazo[1,2-b]pyridazin-2-amine (1.0 g, 3.85 mmol),N,N-dimethylacetamide (8.0 mL) and isobutyryl chloride (0.44 mL, 4.23mmol) as starting materials and in the same manner as in ReferenceExample 5, the title compound (0.93 g, 73%) was obtained as a dark brownpowder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.10 (6H, d, J=6.6 Hz), 2.67-2.74 (1H, m),7.49 (1H, d, J=9.3 Hz), 7.73 (1H, d, J=9.3 Hz), 8.27 (1H, s), 10.87 (1H,s).

Reference Example 12 Production of1-methyl-1H-1,2,3-triazole-5-carboxylic acid

To a solution of ethyl 1-methyl-1H-1,2,3-triazole-5-carboxylate (1.15 g,7.41 mmol) in methanol (17 mL) was added 1N sodium hydroxide (11.5 mL),and the mixture was stirred at room temperature for 1 hr. Methanol wasevaporated under reduced pressure, 1N hydrochloric acid (12 mL) wasadded to the mixture, the precipitated crystals were collected byfiltration and washed with water. The crystals were vacuum dried at 90°C. to give the title compound (148 mg, 16%) as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 4.23 (3H, s), 8.20 (1H, s).

Reference Example 13 Production of1-methyl-1H-1,2,3-triazole-4-carboxylic acid

Using ethyl 1-methyl-1H-1,2,3-triazole-4-carboxylate (1.48 g, 9.54mmol), methanol (22 mL), 1N sodium hydroxide (15 mL) and 1N hydrochloricacid (15 mL) as starting materials and in the same manner as inReference Example 12, the title compound (605 mg, 50%) was obtained as awhite powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 4.09 (3H, s), 8.62 (1H, s), 10.06 (1H, br).

Reference Example 14 Production ofN-(6-iodoimidazo[1,2-b]pyridazin-2-yl)propaneamide

Using 6-iodoimidazo[1,2-b]pyridazin-2-amine (1.0 g, 3.85 mmol),N,N-dimethylacetamide (10 mL) and propionyl chloride (0.37 mL, 4.23mmol) as starting materials and in the same manner as in ReferenceExample 5, the title compound (0.88 g, 72%) was obtained as a dark brownpowder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.08 (3H, d, J=7.5 Hz), 2.39 (2H, q, j=7.5Hz), 7.48 (1H, d, J=9.3 Hz), 7.73 (1H, d, J=9.3 Hz), 8.26 (1H, s), 10.86(1H, s).

Reference Example 15 Production of 3-amino-4-fluorophenol

To a solution of 2-chloro-4-fluoro-5-nitrophenol (3.20 g, 16.7 mmol) inmethanol (60 mL) was added 20 wt % palladium hydroxide on carbon (1.60g) under nitrogen atmosphere. The reaction mixture was stirred at roomtemperature for 8 hr under hydrogen atmosphere. After nitrogenreplacement, triethylamine (2.32 mL, 16.7 mmol) was added to thereaction mixture, and the mixture was filtered through a kiriyamafunnel. Saturated brine was added to the filtrate, and the mixture wasextracted twice with diethyl ether. The extract was dried over anhydrousmagnesium sulfate, and filtrated. The solvent was evaporated underreduced pressure, and the residue was recrystallized from diethylether/hexane to give the title compound (1.40 g, 66%) as pale-browncrystals.

¹H-NMR (CDCl₃, 300 MHz) δ 3.70 (2H, brs), 4.50 (1H, s), 6.10 (1H, dt,J=8.7, 3.0 Hz), 6.26 (1H, dd, J=7.5, 3.0 Hz), 6.81 (1H, dd, J=10.8, 8.7Hz).

Reference Example 16 Production ofN-(6-iodoimidazo[1,2-b]pyridazin-2-yl)-N²,N²-dimethylglycinamide

To a solution of 6-iodoimidazo[1,2-b]pyridazin-2-amine (1040 mg, 4.0mmol) in N-methylpyrrolidone (5.0 mL) was added dimethylaminoacetylchloride hydrochloride (948 mg, 6.0 mmol), and the mixture was stirredat room temperature for 6 hr. The reaction mixture was diluted with 1Naqueous sodium hydroxide solution, and extracted with ethyl acetate. Theorganic layer was concentrated under reduced pressure, and the residuewas purified by silica gel column chromatography (ethylacetate/methanol=100/0→70/30), and precipitated from diisopropyl etherto give the title compound (1019 mg, 74%) as a pale-yellow powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 2.28 (6H, s), 3.16 (2H, s), 7.51 (1H, d,J=9.2 Hz), 7.75 (1H, d, J=9.2 Hz), 8.29 (1H, s), 10.50 (1H, s).

Reference Example 17 Production of2-cyclopropyl-N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)acetamide

To a solution of cyclopropylacetic acid (441 mg, 4.4 mmol) intetrahydrofuran (8.0 mL) were added N,N-dimethylformamide (1 drop) andthionyl chloride (0.32 mL, 4.4 mmol), and the mixture was stirred atroom temperature for 2 hr. The reaction mixture was concentrated underreduced pressure, and dissolved in N,N-dimethylacetamide (2.0 mL). To asolution of 6-iodoimidazo[1,2-b]pyridazin-2-amine (1.04 g, 4.0 mmol) inN,N-dimethylacetamide (6.0 mL) was added dropwise the above-mentionedsolution under ice-cooling. The mixture was stirred at room temperaturefor 2 hr. Under ice-cooling, aqueous sodium hydrogencarbonate solutionwas added to the reaction mixture, and the mixture was extracted withethyl acetate. The extract was washed with saturated brine, dried overanhydrous magnesium sulfate, and filtrated. The solvent was evaporatedunder reduced pressure, and the residue was purified by basic silica gelcolumn chromatography (ethyl acetate/hexane=80/20→100/0), andrecrystallized from ethyl acetate to give the title compound (982 mg,72%) as pale-green crystals.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.10-0.25 (2H, m), 0.45-0.55 (2H, m),1.00-1.15 (1H, m), 2.27 (2H, d, J=6.9 Hz), 7.48 (1H, d, J=9.4 Hz), 7.72(1H, d, J=9.4 Hz), 8.28 (1H, s), 10.82 (1H, s).

Reference Example 18 Production of 3-amino-4-fluorophenyl methylcarbonate hydrochloride

To a solution (20 mL) of 2-chloro-4-fluoro-5-nitrophenyl methylcarbonate (1.00 g, 4.0 mmol) in methanol was added 20% palladiumhydroxide on carbon (0.4 g) under a nitrogen atmosphere. The reactionmixture was stirred under a hydrogen atmosphere at room temperature for5 days. After nitrogen replacement, the catalyst was filtered off. Thesolvent was evaporated from the filtrate under reduced pressure, and theresidue was recrystallized from diethyl ether to give the title compound(759 mg, 86%) as a pale-green powder.

¹H-NMR (CDCl₃, 300 MHz) δ 3.89 (3H, s), 6.75-6.85 (1H, m), 7.05-7.15(2H, m).

Reference Example 19 Production of3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}-4-fluorophenyl methylcarbonate

Using a solution of 3-amino-4-fluorophenyl methyl carbonatehydrochloride (740 mg, 3.34 mmol) and1,3-dimethyl-1H-pyrazole-5-carbonylchloride (556 mg, 3.51 mmol) inN,N-dimethylacetamide (10 mL), and by a reaction in the same manner asin Example 148, the title compound (895 mg, 87%) was obtained as a whitepowder.

¹H-NMR (CDCl₃, 300 MHz) δ 2.30 (3H, s), 3.91 (3H, s), 4.14 (3H, s), 6.45(1H, s), 6.85-6.95 (1H, m), 7.13 (1H, dd, J=9.0 Hz, 10.5 Hz), 7.83 (1H,br s), 8.33 (1H, dd, J=2.7 Hz, 6.6 Hz).

Reference Example 20 Production ofN-(2-fluoro-5-hydroxyphenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide

To a solution of3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}-4-fluorophenyl methylcarbonate (448 mg, 1.46 mmol) in methanol (10 mL) was added 1N aqueoussodium hydroxide solution (2 mL, 2 mmol) under ice-cooling, and themixture was stirred at room temperature for 40 min. Under ice-cooling,1N hydrochloric acid was added to the reaction mixture, and the mixturewas extracted with ethyl acetate. The extract was washed with saturatedbrine, dried over anhydrous magnesium sulfate, and filtrated. Thesolvent was evaporated under reduced pressure, and the residue wasrecrystallized from diethyl ether/hexane to give the title compound (305mg, 84%) as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 2.19 (3H, s), 3.98 (3H, s), 6.56 (1H, m),6.82 (1H, s), 6.97-7.10 (2H, m), 9.47 (1H, s), 9.85 (1H, s).

Reference Example 21 Production of 1,4-dimethyl-1H-pyrazole-3-carboxylicacid

Using ethyl 1,4-dimethyl-1H-pyrazole-3-carboxylate (440 mg, 2.62 mmol),1N aqueous sodium hydroxide solution (3 mL, 3 mmol) and ethanol (3 mL),and by a reaction in the same manner as in Reference Example 20, thetitle compound (152 mg, 41%) was obtained as pale-yellow crystals.

¹H-NMR (CDCl₃, 300 MHz) δ 2.30 (3H, s), 3.92 (3H, s), 7.21 (1H, s).

Reference Example 22 Production of 1,4-dimethyl-1H-pyrazole-5-carboxylicacid

Using ethyl 1,4-dimethyl-1H-pyrazole-5-carboxylate (565 mg, 3.36 mmol),1N aqueous sodium hydroxide solution (4 mL, 4 mmol) and ethanol (4 mL),and by a reaction in the same manner as in Reference Example 20, thetitle compound (261 mg, 55%) was obtained as colorless crystals.

¹H-NMR (CDCl₃, 300 MHz) δ 2.31 (3H, s), 4.16 (3H, s), 7.34 (1H, s).

Reference Example 23 Production of3-{[(1,3-dimethyl-1H-pyrazol-5-yl)methyl]amino}-4-methylphenol

To a solution of 3-amino-4-methylphenol (930 mg, 7.5 mmol) inN,N-dimethylacetamide (10 mL) was added a solution of1,3-dimethyl-1H-pyrazole-5-carbonylchloride (1370 mg, 8.7 mmol) in N,N-dimethylacetamide (5 mL), and the mixture was stirred at 0° C. for 20min. To the mixture were added ethyl acetate/tetrahydrofuran, saturatedaqueous sodium hydrogencarbonate solution, and the aqueous layer wasextracted 4 times with ethyl acetate/tetrahydrofuran. Combined organiclayer was washed with water and saturated brine, dried over anhydroussodium sulfate, and filtrated. The filtrate was concentrated underreduced pressure, and the residue was washed with ethyl acetate/hexaneto giveN-(5-hydroxy-2-methylphenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide(1170 mg, 63%) as a white solid. To a suspension of lithium aluminumhydride (1130 mg, 24 mmol) in tetrahydrofuran (35 mL) was slowly addeddropwise a solution ofN-(5-hydroxy-2-methylphenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide(1170 mg, 4.8 mmol) in tetrahydrofuran (10 mL) under ice-cooling. Afterdropwise addition, the reaction mixture was heated under reflux for 5hr. A saturated aqueous sodium sulfate solution was added to the mixtureunder cooling, magnesium sulfate was added and the insoluble materialwas filtrated. The filtrate was concentrated under reduced pressure, andthe residue was washed with ethyl acetate/hexane to give the titlecompound (570 mg, 52%) as a white solid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.98 (3H, s), 2.06 (3H, s), 3.72 (3H, s),4.21 (2H, d, J=5.7 Hz), 5.23 (1H, t, J=5.7 Hz), 5.89 (1H, s), 5.93 (1H,dd, J=8.0, 2.3 Hz), 5.97 (1H, d, J=2.3 Hz), 6.71 (1H, d, J=8.3 Hz), 8.73(1H, s).

Reference Example 24 Production of 2-methyl-1H-indole-6-ol

To a suspension of lithium aluminum hydride (3.7 g, 97 mmol) in1,4-dioxane (97 mL) was slowly added dropwise a solution of methyl6-methoxy-1H-indole-2-carboxylate (2.0 g, 9.8 mmol) in 1,4-dioxane (30mL) under ice-cooling. After dropwise addition, the reaction mixture washeated under reflux for 24 hr. A saturated aqueous sodium sulfatesolution was added to the mixture under cooling, magnesium sulfate wasadded and the insoluble material was filtrated. The filtrate wasconcentrated under reduced pressure, and the residue was recrystallizedfrom hexane to give 6-methoxy-2-methyl-1H-indole (1.0 g, 6.5 mmol) as ayellow solid. To a solution of 6-methoxy-2-methyl-1H-indole (1.0 g, 6.2mmol) in acetic acid (15 mL) was added 48% aqueous hydrogen bromide (31mL) at room temperature, and the reaction mixture was heated underreflux for 3 hr. The solvent was evaporated under reduced pressure,ethyl acetate/tetrahydrofuran and saturated aqueous sodiumhydrogencarbonate solution were added to the residue. The aqueous layerwas extracted with ethyl acetate/tetrahydrofuran (×3). Combined organiclayer was washed with saturated brine, dried over anhydrous sodiumsulfate, and filtrated. The filtrate was concentrated under reducedpressure, and the residue was washed with ethyl acetate/hexane to givethe title compound (600 mg, 65%) as a white solid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 2.29 (3H, d, J=0.8 Hz), 5.88-5.95 (1H, m),6.43 (1H, dd, J=8.3, 2.3 Hz), 6.63 (1H, d, J=2.3 Hz), 7.12 (1H, d, J=8.3Hz), 8.70 (1H, s), 10.45 (1H, br, s).

Reference Example 25 Production of4-chloro-3-{[(1,3-dimethyl-1H-pyrazol-5-yl)methyl]amino}phenol

In the same manner as in Reference Example 23 and using3-amino-4-chlorophenol (920 mg, 6.4 mmol),1,3-dimethyl-1H-pyrazole-5-carbonylchloride (1170 mg, 7.4 mmol) andN,N-dimethylacetamide (13 mL) as starting materials,N-(2-chloro-5-hydroxyphenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide(1190 mg, 4.5 mmol) was obtained. Using lithium aluminum hydride (1060mg, 22 mmol),N-(2-chloro-5-hydroxyphenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide(1190 mg, 4.5 mmol) and tetrahydrofuran (40 mL) as starting materials,the title compound (810 mg, 72%) was obtained as a brown solid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 2.06 (3H, s), 3.72 (3H, s), 4.29 (2H, d,J=5.7 Hz), 5.73 (1H, t, J=5.7 Hz), 5.87 (1H, s), 6.02 (1H, dd, J=8.3,2.7 Hz), 6.11 (1H, d, J=2.7 Hz), 6.99 (1H, d, J=8.3 Hz), 9.27 (1H, s).

Reference Example 26 Production of1-(2-methoxyethyl)-3-methyl-1H-pyrazole-5-carboxylic acid

To a suspension of sodium hydride (310 mg, 7.8 mmol) inN,N-dimethylformamide (10 mL) was slowly added a solution of ethyl3-methyl-1H-pyrazole-5-carboxylate (1000 mg, 6.5 mmol) inN,N-dimethylformamide (5 mL) under ice-cooling, and the mixture wasstirred at 0° C. for 10 min, then at room temperature for 20 min. To thereaction mixture was added a solution of 1-bromo-2-methoxyethane (1090mg, 7.8 mmol) in N,N-dimethylformamide (4 mL), and the mixture wasstirred at room temperature for 7 hr. The solvent was evaporated underreduced pressure, and ethyl acetate/tetrahydrofuran and water were addedto the residue. The aqueous layer was extracted with ethylacetate/tetrahydrofuran (×3). Combined organic layer was washed withsaturated brine, dried over anhydrous sodium sulfate, and filtrated. Thefiltrate was concentrated under reduced pressure, and the residue waspurified by silica gel column chromatography (ethylacetate/hexane=5/95→70/30) to give ethyl1-(2-methoxyethyl)-3-methyl-1H-pyrazole-5-carboxylate (430 mg, 2.0 mmol)as a colorless liquid. To a solution of the obtained ethyl1-(2-methoxyethyl)-3-methyl-1H-pyrazole-5-carboxylate (430 mg, 2.0 mmol)in tetrahydrofuran (6 mL) was added 8N aqueous sodium hydroxide solution(1.3 mL), and the mixture was stirred at room temperature for 3 hr. 1NHydrochloric acid (13 mL) and ethyl acetate were added to the reactionmixture, and the aqueous layer was extracted with ethyl acetate (×3).Combined organic layer was washed with saturated brine, dried overanhydrous sodium sulfate, and filtrated. The filtrate was concentratedunder reduced pressure, and the residue was washed with ethylacetate/hexane to give the title compound (310 mg, 83%) as a whitesolid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 2.15 (3H, s), 3.17 (3H, s), 3.61 (2H, t,J=5.8 Hz), 4.55 (2H, t, J=5.8 Hz), 6.56 (1H, s), 13.19 (1H, br. s).

Reference Example 27 Production ofN-(3-aminophenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide

To a solution of 3-nitroaniline (1.0 g, 7.2 mmol) inN,N-dimethylacetamide (6 mL) was added a solution of1,3-dimethyl-1H-pyrazole-5-carbonylchloride (1260 mg, 8.0 mmol) inN,N-dimethylacetamide (2 mL), and the mixture was stirred at roomtemperature for 30 min. Water (200 mL) was added to the mixture underice-cooling, and the mixture was filtrated. The obtained solid waswashed with water and diethyl ether to give1,3-dimethyl-N-(3-nitrophenyl)-1H-pyrazole-5-carboxamide (1850 mg, 7.1mmol). To a solution of the obtained1,3-dimethyl-N-(3-nitrophenyl)-1H-pyrazole-5-carboxamide (1850 mg, 7.1mmol) in ethanol (50 mL) was added 10% palladium/carbon (190 mg).Hydrazine monohydrate (1090 mg, 22 mmol) was slowly added to the mixtureat room temperature and the mixture was stirred at 60° C. for 1 hr. Thereaction mixture was filtrated, and the filtrate was evaporated underreduced pressure. To the residue were added ethyl acetate and water, andthe aqueous layer was extracted with ethyl acetate (×4). Combinedorganic layer was washed with saturated brine, dried over anhydroussodium sulfate, and filtrated. The filtrate was concentrated underreduced pressure, and the residue was washed with ethyl acetate/hexaneto give the title compound (1650 mg, 99%) as a pale-yellow solid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 2.19 (3H, s), 3.98 (3H, s), 5.09 (2H, s),6.31 (1H, d, J=9.1 Hz), 6.76-6.83 (2H, m), 6.95 (1H, t, J=8.0 Hz),7.03-7.08 (1H, m), 9.81 (1H, s).

Reference Example 28 Production of(2E)-N-(5-hydroxy-2-methylphenyl)but-2-ene amide

In the same manner as in Example 259 and using (2E)-but-2-enoic acid(1680 mg, 19 mmol), tetrahydrofuran (5 mL), N,N-dimethylformamide (1drop), oxalyl chloride (1670 μL, 19 mmol), 3-amino-4-methylphenol (2000mg, 16 mmol) and N,N-dimethylacetamide (35 mL) as starting materials,the title compound (1830 mg, 59%) was obtained as a white solid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.85 (3H, dd, J=7.0, 1.7 Hz), 2.07 (3H, s),6.22 (1H, d, J=15.5 Hz), 6.47 (1H, dd, J=8.3, 2.5 Hz), 6.68-6.83 (1H,m), 6.95 (1H, d, J=8.3 Hz), 7.02 (1H, s), 9.05 (1H, s), 9.16 (1H, s).

Reference Example 29 Production ofN-(5-hydroxy-2-methylphenyl)-1,4-dimethyl-4,5-dihydro-1H-pyrazole-3-carboxamide

A mixture of (2E)-N-(5-hydroxy-2-methylphenyl)but-2-ene amide (1830 mg,9.6 mmol) and 3-methyl-1,2,3-oxadiazol-3-ium-5-olate (4 mL) was stirredat 150° C. for 2 days. The reaction mixture was purified by silica gelcolumn chromatography (ethyl acetate/hexane=5/95→60/40) to give thetitle compound (351 mg, 15%) as a pale-yellow solid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.15 (3H, d, J=6.4 Hz), 2.07 (3H, s), 2.91(3H, s), 3.04-3.11 (1H, m), 3.23-3.33 (2H, m), 6.47 (1H, dd, J=8.3, 2.7Hz), 6.97 (1H, d, J=8.3 Hz), 7.13 (1H, d, J=2.7 Hz), 8.94 (1H, s), 9.22(1H, s).

Reference Example 30 Production of methyl 3-(cyanomethyl)benzoate

To a solution of methyl 3-(bromomethyl)benzoate (10.0 g, 44 mmol) inacetonitrile (100 mL) were added potassium cyanide (5.7 g, 87 mmol) and18-crown-6 (1.0 g), and the mixture was stirred at room temperature for3 days. The reaction mixture was filtrated, the solvent was evaporatedunder reduced pressure, and the residue was purified by silica gelcolumn chromatography (ethyl acetate/hexane=5/95→30/70). The combinedsolution was concentrated under reduced pressure to give the titlecompound (7.0 g, 91%) as a colorless oil.

¹H-NMR (DMSO-d₆, 300 MHz) δ 3.88 (3H, s), 4.17 (2H, s), 7.57 (1H, t,J=7.6 Hz), 7.61-7.69 (1H, m), 7.88-7.95 (1H, m), 7.97 (1H, br s).

Reference Example 31 Production of methyl3-(1-cyano-1-methylethyl)benzoate

To a solution of methyl 3-(cyanomethyl)benzoate (7.0 g, 40 mmol) indimethylsulfoxide (80 mL) was slowly added sodium hydride (60% in oil,4.8 g, 120 mmol) under cooling at not more than 25° C. The reactionmixture was stirred at room temperature for 20 min. To the mixture wasadded methyl iodide (7.5 mL, 120 mmol), and the mixture was stirred atroom temperature for 16 hr. Under ice-cooling, the reaction mixture wasdiluted with water. The mixture was extracted with ethyl acetate, andthe organic layer was washed with water and saturated brine, dried overanhydrous sodium sulfate, and filtrated. The solvent was evaporatedunder reduced pressure, and the residue was purified by silica gelcolumn chromatography (ethyl acetate/hexane=5/95→50/50). The combinedsolution was concentrated under reduced pressure to give the titlecompound (6.4 g, 79%) as a colorless oil.

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.72 (6H, s), 3.89 (3H, s), 7.61 (1H, t,J=7.8 Hz), 7.84 (1H, ddd, J=7.8, 2.1, 1.2 Hz), 7.95 (1H, dt, J=7.8, 1.2Hz), 8.08 (1H, t, J=1.5 Hz).

Reference Example 32 Production of 3-(1-cyano-1-methylethyl)benzoic acid

To a solution of methyl 3-(1-cyano-1-methylethyl)benzoate (2.8 g, 14mmol) in tetrahydrofuran (30 mL) were added lithiumhydroxide-monohydrate (0.98 g, 24 mmol), methanol (10 mL) and water (10mL), and the mixture was stirred at room temperature for 18 hr. Thesolvent was evaporated under reduced pressure, and the residue wasdiluted with water (15 mL). The mixture was adjusted to pH 3 by slowlyadding 1N hydrochloric acid. The precipitated white precipitate wascollected by filtration, washed with water, and air-dried to give thetitle compound (2.5 g, 98%) as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.72 (6H, s), 7.57 (1H, t, J=7.8 Hz), 7.78(1H, dq, J=7.8, 1.5 Hz), 7.92 (1H, dt, J=7.8, 1.5 Hz), 8.08 (1H, t,J=1.5 Hz), 13.19 (1H, s).

Reference Example 33 Production of methyl3-(4-cyanotetrahydro-2H-pyran-4-yl)benzoate

Using methyl 3-(cyanomethyl)benzoate (1.0 g, 5.7 mmol), sodium hydride(60% in oil, 0.69 g, 17 mmol), bis(2-bromoethyl)ether (1.8 g, 6.9 mmol)and dimethyl sulfoxide (12 mL) as starting materials and in the samemanner as in Reference Example 31, the title compound (650 mg, 46%) wasobtained as a colorless oil.

¹H-NMR (DMSO-d₆, 300 MHz) δ 2.02-2.21 (4H, m), 3.61-3.75 (2H, m), 3.89(3H, s), 3.98-4.09 (2H, m), 7.64 (1H, t, J=7.8 Hz), 7.83-7.91 (1H, m),7.93-8.01 (1H, m), 8.10 (1H, t, J=1.7 Hz).

Reference Example 34 Production of3-(4-cyanotetrahydro-2H-pyran-4-yl)benzoic acid

To a solution of methyl 3-(4-cyanotetrahydro-2H-pyran-4-yl)benzoate(0.62 g, 2.5 mmol) in tetrahydrofuran (6.0 mL) were added lithiumhydroxide-monohydrate (0.18 g, 4.3 mmol), methanol (2.0 mL) and water(2.0 mL), and the mixture was stirred at room temperature for 12 hr. Thesolvent was evaporated under reduced pressure, and the residue wasdiluted with water (5.0 mL). The mixture was adjusted to pH 3 by slowlyadding 1N hydrochloric acid. The mixture was extracted with ethylacetate, and the organic layer was washed with water and saturatedbrine, dried over anhydrous sodium sulfate, and filtrated. The solventwas evaporated under reduced pressure to give the title compound (0.48g, 83%) as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 2.00-2.23 (4H, m), 3.57-3.77 (2H, m),3.94-4.10 (2H, m), 7.61 (1H, t, J=7.8 Hz), 7.77-7.87 (1H, m), 7.90-8.00(1H, m), 8.05-8.12 (1H, m), 13.20 (1H, br s).

Reference Example 35 Production of 5-bromopyridine-3-ol

To a solution of 3-bromo-5-methoxypyridine (5.0 g, 27 mmol) in aceticacid (15 mL) was added 48% hydrobromic acid (23 mL), and the reactionmixture was heated under reflux for 16 hr. The mixture was allowed tocool to room temperature, and the solvent was evaporated under reducedpressure. The residue was adjusted to pH9-10 by adding 8N aqueous sodiumhydroxide solution. The obtained aqueous solution was washed withdiethyl ether, and the pH was adjusted to 5-6 by adding 6N hydrochloricacid. The obtained precipitate was collected by filtration, and washedwith diisopropyl ether to give the title compound (2.8 g, 61%) as apale-yellow powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 7.40 (1H, t, J=2.1 Hz), 8.12-8.15 (2H, m),10.47 (1H, br. s).

Reference Example 36 Production of methyl 3-(1-cyanocyclopropyl)benzoate

Using methyl 3-(cyanomethyl)benzoate (1.5 g, 8.6 mmol), sodium hydride(60% in oil, 1.0 g, 26 mmol), 1,2-dibromoethane (2.4 g, 13 mmol) anddimethyl sulfoxide (30 mL) as starting materials and in the same manneras in Reference Example 31, the title compound (1.3 g, 76%) was obtainedas a colorless oil.

¹H-NMR (CDCl₃, 300 MHz) δ 1.38-1.56 (2H, m), 1.74-1.82 (2H, m), 3.93(3H, s), 7.40-7.49 (1H, m), 7.55-7.62 (1H, m), 7.88 (1H, t, J=1.5 Hz),7.96 (1H, dt, J=7.8, 1.5 Hz).

Reference Example 37 Production of 3-(1-cyanocyclopropyl)benzoic acid

To a solution of methyl 3-(1-cyanocyclopropyl)benzoate (1.3 g, 6.4 mmol)in tetrahydrofuran (12 mL) were added lithium hydroxide-monohydrate(0.44 g, 11 mmol), methanol (4.0 mL) and water (6.0 mL), and the mixturewas stirred at room temperature for 14 hr. The solvent was evaporatedunder reduced pressure, and the residue was diluted with water (5.0 mL).The mixture was adjusted to pH 5 by slowly adding 1N hydrochloric acid.The precipitated white precipitate was collected by filtration, washedwith water, and air-dried to give the title compound (0.73 g, 61%) as awhite powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.50-1.62 (2H, m), 1.76-1.86 (2H, m),7.41-7.59 (2H, m), 7.82-7.97 (2H, m), 13.19 (1H, br. s.).

Reference Example 38 Production of methyl 3-(1-cyanocyclohexyl)benzoate

Using methyl 3-(cyanomethyl)benzoate (1.5 g, 8.6 mmol), sodium hydride(60% in oil, 1.0 g, 26 mmol), 1,5-dibromopentane (3.0 g, 13 mmol) anddimethyl sulfoxide (30 mL) as starting materials and in the same manneras in Reference Example 31, the title compound (1.4 g, 68%) was obtainedas a colorless oil.

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.23-1.46 (1H, m), 1.53-2.17 (9H, m), 3.88(3H, s), 7.61 (1H, t, J=7.8 Hz), 7.80-7.88 (1H, m), 7.95 (1H, dt, J=7.8,1.2 Hz), 8.10 (1H, t, J=1.8 Hz).

Reference Example 39 Production of 3-(1-cyanocyclohexyl)benzoic acid

Using methyl 3-(1-cyanocyclohexyl)benzoate (1.3 g, 5.3 mmol), lithiumhydroxide-monohydrate (0.52 g, 13 mmol), tetrahydrofuran (18 mL),methanol (6.0 mL) and water (6.0 mL) as starting materials and in thesame manner as in Reference Example 37, the title compound (1.1 g, 88%)was obtained as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.21-1.43 (1H, m), 1.52-2.17 (9H, m), 7.58(1H, t, J=7.8 Hz), 7.80 (1H, dq, J=7.8, 1.2 Hz), 7.92 (1H, dt, J=7.8,1.2 Hz), 8.09 (1H, t, J=1.8 Hz).

Reference Example 40 Production of methyl 3-(1-cyanocyclobutyl)benzoate

Using methyl 3-(cyanomethyl)benzoate (1.8 g, 10 mmol), sodium hydride(60% in oil, 1.2 g, 30 mmol), 1,3-dibromopropane (3.0 g, 15 mmol) anddimethyl sulfoxide (30 mL) as starting materials and in the same manneras in Reference Example 31, the title compound (0.91 g, 42%) wasobtained as a colorless oil.

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.92-2.12 (1H, m), 2.18-2.41 (1H, m),2.56-2.91 (4H, m), 3.88 (3H, s), 7.59-7.66 (1H, m), 7.75-7.83 (1H, m),7.91-8.02 (2H, m).

Reference Example 41 Production of 3-(1-cyanocyclobutyl)benzoic acid

Using methyl 3-(1-cyanocyclobutyl)benzoate (0.9 g, 4.2 mmol), lithiumhydroxide-monohydrate (0.26 g, 6.3 mmol), tetrahydrofuran (9.0 mL),methanol (3.0 mL) and water (4.0 mL) as starting materials and in thesame manner as in Reference Example 37, the title compound (0.73 g, 86%)was obtained as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.93-2.13 (1H, m), 2.20-2.42 (H, m),2.56-2.90 (4H, m), 7.59 (1H, t, J=7.8 Hz), 7.68-7.81 (1H, m), 7.85-8.01(2H, m).

Reference Example 42 Production of2-methyl-2-(3-nitrophenyl)propanenitrile

To a two-phase solution of (3-nitrophenyl)acetonitrile (5.0 g, 31 mmol)and tetraethylammoniumbromide (600 mg) in 2N aqueous sodium hydroxide(47 mL, 93 mmol) and methylene chloride (50 mL) was added methyl iodide(8.0 mL, 130 mmol), and the mixture was stirred at room temperature for12 hr. The reaction mixture was diluted with water and extracted withethyl acetate. The organic layer was washed with saturated brine, driedover anhydrous sodium sulfate, and filtrated. The solvent was evaporatedunder reduced pressure, and the residue was purified by silica gelcolumn chromatography (ethyl acetate/hexane=2/98→10/90) to give thetitle compound (0.38 g, 6.5%) as a yellow oil.

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.76 (6H, s), 7.76 (1H, t, J=8.0 Hz), 8.04(1H, dd, J=7.8, 0.8 Hz), 8.24 (1H, d, J=8.3 Hz), 8.32 (1H, s).

Reference Example 43 Production of2-(3-aminophenyl)-2-methylpropanenitrile

To a solution of 2-methyl-2-(3-nitrophenyl)propanenitrile (0.35 g, 1.8mmol) in ethyl acetate (10 mL) was added 10% palladium/carbon (35 mg),and the mixture was stirred for 10 hr under hydrogen atmosphere. Theresidual catalyst was filtered through celite, and washed with ethylacetate. The filtrate was concentrated under reduced pressure to givethe title compound (0.35 g, 1.8 mmol) as a pale-yellow oil.

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.61 (6H, s), 5.21 (2H, br. s), 6.46-6.55(1H, m), 6.56-6.63 (1H, m), 6.71 (1H, t, J=2.1 Hz), 7.04 (1H, t, J=7.8Hz).

Reference Example 44 Production of2-methyl-2-(4-nitrophenyl)propanenitrile

To a two-phase solution of (4-nitrophenyl)acetonitrile (5.0 g, 31 mmol)and tetraethylammoniumbromide (2.0 g) in 2N aqueous sodium hydroxide (75mL, 150 mmol) and methylene chloride (50 mL) was added methyl iodide(9.6 mL, 150 mmol), and the mixture was stirred at room temperature for4 hr. To the reaction mixture were added 2N aqueous sodium hydroxidesolution (10 mL, 20 mmol) and methyl iodide (1.5 mL, 24 mmol), and themixture was further stirred for 2 hr. The reaction mixture was dilutedwith water and extracted with ethyl acetate. The organic layer waswashed with saturated brine, dried over anhydrous sodium sulfate, andfiltrated. The solvent was evaporated under reduced pressure, and theresidue was purified by silica gel column chromatography (ethylacetate/hexane=5/95→10/90) to give the title compound (3.8 g, 65%) as apale-yellow oil.

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.75 (6H, s), 7.79-7.88 (2H, m), 8.25-8.34(2H, m).

Reference Example 45 2-(4-aminophenyl)-2-methylpropanenitrile

To a solution of 2-methyl-2-(4-nitrophenyl)propanenitrile (0.95 g, 5.0mmol) in ethyl acetate (10 mL) was added 10% palladium/carbon (100 mg),and the mixture was stirred at room temperature for 14 hr under hydrogenatmosphere. The residual catalyst was filtered through celite, andwashed with ethyl acetate. The filtrate was concentrated under reducedpressure to give the title compound (0.81 g, 99%) as a pale-yellow oil.

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.59 (6H, s), 5.14 (2H, br. s), 6.57 (2H, d,J=8.7 Hz), 7.12 (2H, d, J=8.7 Hz).

Reference Example 46 Production of methyl 3-(1-cyanoethyl)benzoate

To a solution of 3-(1-cyanoethyl)benzoic acid (2.0 g, 11 mmol) inmethanol (20 mL) was added conc. sulfuric acid (0.2 mL), and the mixturewas stirred at 60° C. for 8 hr. The reaction mixture was concentratedunder reduced pressure, and neutralized with saturated aqueous sodiumhydrogencarbonate solution. The mixture was diluted with water andextracted with ethyl acetate. The organic layer was washed withsaturated brine, dried over anhydrous sodium sulfate, and filtrated. Thesolvent was evaporated under reduced pressure to give the title compound(1.9 g, 89%) as a colorless oil.

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.57 (3H, d, J=7.2 Hz), 3.88 (3H, s), 4.46(1H, q, J=7.2 Hz), 7.59 (1H, t, J=7.8 Hz), 7.68-7.76 (1H, m), 7.94 (1H,dt, J=7.8, 1.5 Hz), 8.00 (1H, t, J=1.8 Hz).

Reference Example 47 Production of methyl3-(1-cyano-2-cyclopropyl-1-methylethyl)benzoate

To a solution of methyl 3-(1-cyanoethyl)benzoate (1.5 g, 7.9=mol) inacetonitrile (20 mL) were added sodium methoxide (0.95 g, 17 mmol) and(bromomethyl)cyclopropane (1.3 g, 9.5 mmol), and the reaction mixturewas stirred at room temperature for 30 min. To the reaction mixture wasadded sodium hydride (60% in oil, 0.7 g, 17 mmol) under ice-cooling, andthe mixture was stirred at room temperature for 16 hr. The mixture wasdiluted with diethyl ether, and washed with 5% aqueous sodiumhydrogencarbonate solution and saturated brine. The organic layer wasdried over anhydrous sodium sulfate, and filtrated. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography (ethyl acetate/hexane=5/95→40/60) togive the title compound (129 mg, 6.7%) as a colorless oil.

¹H-NMR (DMSO-d₆, 300 MHz) δ −0.10-0.03 (1H, m), 0.21 (1H, dt, J=4.9, 9.1Hz), 0.26-0.39 (1H, m), 0.39-0.50 (1H, m), 0.51-0.66 (1H, m), 1.70-1.77(3H, m), 1.77-1.89 (1H, m), 1.92-2.03 (1H, m), 3.88 (3H, s), 7.55-7.67(1H, m), 7.77-7.86 (1H, m), 7.95 (1H, d, J=7.7 Hz), 8.08-8.13 (1H, m).

Reference Example 48 Production of3-(1-cyano-2-cyclopropyl-1-methylethyl)benzoic acid

To a solution of methyl 3-(1-cyano-2-cyclopropyl-1-methylethyl)benzoate(120 mg, 0.49 mmol) in tetrahydrofuran/methanol/water (=3.0 mL/1.0mL/1.0 mL) was added lithium hydroxide monohydrate (40 mg, 0.99 mmol),and the reaction mixture was stirred at room temperature for 4 hr. Themixture was concentrated under reduced pressure, and the obtainedaqueous solution was adjusted to pH 5 by adding 1N hydrochloric acid.The mixture was concentrated under reduced pressure, and the residue waspurified by silica gel column chromatography (ethylacetate/hexane=50/50→100/0) to give the title compound (76 mg, 66%) as acolorless oil.

¹H NMR (DMSO-d₆, 300 MHz) δ −0.04-0.09 (1H, m), 0.18-0.31 (1H, m),0.36-0.49 (1H, m), 0.49-0.62 (1H, m), 0.64-0.82 (1H, m), 1.73-1.87 (2H,m), 1.91-2.03 (2H, m), 7.44-7.63 (1H, m), 7.79-7.86 (1H, m), 8.09 (1H,d, J=7.9 Hz), 8.15-8.22 (1H, m), 11.25-12.45 (1H, br. s).

Reference Example 49 Production of ethyl2-(cyanomethyl)-1,3-thiazole-4-carboxylate

To a solution of ethyl 3-bromo-2-oxopropanate (21 g, 110 mmol) inN,N-dimethylformamide (50 mL) was added a solution of2-cyanoethanethioamide (10 g, 100 mmol) in N,N-dimethylformamide (50 mL)under ice-cooling, and the reaction mixture was stirred at roomtemperature for 12 hr. The mixture was concentrated under reducedpressure, and the obtained residue was dissolved in ethyl acetate, andwashed with 5% aqueous sodium hydrogencarbonate solution and saturatedbrine. The organic layer was dried over anhydrous sodium sulfate andfiltrated. The solvent was evaporated under reduced pressure, and theresidue was purified by silica gel column chromatography (ethylacetate/hexane=20/80→60/40) to give the title compound (5.1 g, 26%) as ayellow powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.31 (3H, t, J=7.2 Hz), 4.31 (2H, q, J=7.2Hz), 4.63 (2H, s), 8.53 (1H, s).

Reference Example 50 Production of ethyl2-(1-cyano-1-methylethyl)-1,3-thiazole-4-carboxylate

To a solution of ethyl 2-(cyanomethyl)-1,3-thiazole-4-carboxylate (2.0g, 10 mmol) in dimethylsulfoxide (20 mL) was added sodium hydride (60%in oil, 1.6 g, 41 mmol), and the mixture was stirred at room temperaturefor 30 min. Under cooling, a solution of methyl iodide (2.5 mL, 41 mmol)in dimethylsulfoxide (10 mL) was added dropwise to the mixture, and themixture was stirred at room temperature for 6 hr. Water was added to themixture under cooling, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine, dried over anhydroussodium sulfate, and filtrated. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography (ethyl acetate/hexane=5/95→50/50) to give the titlecompound (0.90 g, 39%) as a pale-yellow oil.

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.31 (3H, t, J=7.2 Hz), 1.83 (6H, s), 4.33(2H, q, J=7.2 Hz), 8.59 (1H, s).

Reference Example 51 Production of2-(1-cyano-1-methylethyl)-1,3-thiazole-4-carboxylic acid

To a solution of ethyl2-(1-cyano-1-methylethyl)-1,3-thiazole-4-carboxylate (0.9 g, 4.0 mmol)in tetrahydrofuran/methanol/water (=12 mL/4.0 mL/4.0 mL) was addedlithium hydroxide monohydrate (330 mg, 8.0 mmol), and the reactionmixture was stirred at room temperature for 10 hr. The mixture wasconcentrated under reduced pressure, and the obtained aqueous solutionwas adjusted to pH 5 by adding 1N hydrochloric acid. The mixture wasextracted with ethyl acetate, and the organic layer was washed withsaturated brine, dried over anhydrous sodium sulfate, and filtrated. Thesolvent was evaporated under reduced pressure to give the title compound(256 mg, 53%) as a white powder.

¹H NMR (DMSO-d, 300 MHz₆) δ 1.82 (6H, s), 8.43 (1H, s).

Reference Example 52 Production of 5-amino-2-bromophenol

4-Bromo-3-methoxyaniline (5.0 g, 25 mmol) was added to 48% hydrobromicacid (20 mL), and the reaction mixture was stirred at 80° C. for 16 hr.After completion of the reaction, the mixture was allowed to cool toroom temperature, and adjusted to pH 7-8 by adding 8N aqueous sodiumhydroxide solution. The mixture was extracted with ethyl acetate, andthe obtained organic layer was washed with water and saturated brine,dried over anhydrous sodium sulfate, and filtrated. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography (ethyl acetate/hexane=10/90→100/0) togive the title compound (2.0 g, 43%) as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 5.10 (2H, s), 5.97 (1H, dd, J=8.4, 52.4 Hz),6.19 (1H, d, J=2.4 Hz), 6.99 (1H, d, J=8.4 Hz), 9.64 (1H, s).

Reference Example 53 Production of 2,2,2-trichloroethyl(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)carbamate

To a two-phase solution of 3-tert-butyl-1-phenyl-1H-pyrazol-5-amine (5.0g, 23 mmol) in ethyl acetate (45 mL)/3N aqueous sodium hydroxide (20 mL)was added 2,2,2-trichloroethyl chlorocarbonate (4.5 mL, 33 mmol) underice-cooling, and the mixture was stirred at room temperature for 2 hr.The obtained organic layer was washed with 5% aqueous sodiumhydrogencarbonate, water and saturated brine, dried over anhydroussodium sulfate, and filtrated. The solvent was evaporated under reducedpressure to give the title compound (5.0 g, 55%) as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.28 (9H, s), 4.85 (2H, br. s), 6.30 (1H,s), 7.28-7.53 (5H, m).

Reference Example 54 Production of(6-iodoimidazo[1,2-b]pyridazin-2-yl)methanol

To a solution of 3-amino-6-iodopyridazine (2.0 g, 9.0 mmol) in ethanol(40 mL) was added 3-chloro-2-oxopropyl acetate (2.73 g, 18.1 mmol), andthe mixture was heated under reflux for 24 hr. After cooling the mixtureto room temperature, saturated aqueous sodium hydrogencarbonate solutionwas added to the mixture, and the mixture was extracted with ethylacetate/tetrahydrofuran. The extract was washed with saturated brine,dried over anhydrous sodium sulfate, and filtrated. The solvent wasevaporated under reduced pressure, and the residue was collected byfiltration and washed with ethyl acetate/hexane to give the titlecompound (498 mg, 20%) as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 4.62 (2H, d, J=5.6 Hz), 5.33 (1H, t, J=5.6Hz), 7.49 (1H, d, J=9.3 Hz), 7.80 (1H, d, J=9.3 Hz), 8.14 (1H, s).

Reference Example 55 Production of methyl5-methyl-1,3-thiazole-4-carboxylate

To a solution of methyl 2-amino-5-methyl-1,3-thiazole-4-carboxylate(2.15 g, 12.5 mmol) in tetrahydrofuran (60 mL) was slowly addedtert-butyl nitrite (2.23 mL, 18.7 mmol) with stirring at 50° C., and themixture was stirred at 60° C. for 2 hr. The mixture was diluted withwater (100 mL), and extracted with ethyl acetate (100 mL×2). The organiclayer was concentrated under reduced pressure, and the residue waspurified by silica gel column chromatography (hexane/ethylacetate=80/20→0/100) to give the title compound (1.17 g, yield 60%).

¹H-NMR (DMSO-d₆, 300 MHz) δ 2.72 (3H, s), 3.82 (3H, s), 8.90 (1H, s).

Reference Example 56 Production of 5-methyl-1,3-thiazole-4-carboxylicacid

To a solution of methyl 5-methyl-1,3-thiazole-4-carboxylate (1.17 g, 7.4mmol) in methanol (15 mL) was added 8N aqueous sodium hydroxide solution(2.00 mL), and the mixture was stirred at room temperature for 18 hr. 6NHydrochloric acid (2.67 mL) was added to the mixture, and the mixturewas concentrated under reduced pressure. Water was added to the residue,and the precipitate was collected by filtration, and washed with water.The precipitate was suspended in a mixed solvent of ethyl acetate (9 mL)and ethanol (1 mL), and the mixture was stirred at 80° C. for 3 min.After allowing to cool to room temperature, the precipitate wascollected by filtration, washed with ethyl acetate, and dried underreduced pressure to give the title compound (531 mg, yield 50%) as apale-yellow solid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 2.71 (3H, s), 8.87 (1H, s), 12.88 (1H, brs).

Reference Example 57 Production of methyl3-methoxy-1-methyl-1H-pyrazole-5-carboxylate

A mixture of methyl 3-hydroxy-1-methyl-1H-pyrazole-5-carboxylate (2.34g, 15.0 mmol), iodomethane (3.19 g, 22.5 mmol), potassium carbonate(4.15 g, 30.0 mmol) and N,N-dimethylformamide (15 mL) was stirred atroom temperature for 18 hr. The mixture was diluted with water (50 mL),and extracted with ethyl acetate (50 mL×3). The organic layer was washedwith water (10 mL×2), and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane/ethylacetate=100/0→50/50) to give the title compound (2.01 g, yield 79%) as awhite solid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 3.78 (3H, s), 3.81 (3H, s), 3.94 (3H, s),6.27 (1H, s).

Reference Example 58 Production of3-methoxy-1-methyl-1H-pyrazole-5-carboxylic acid

To a solution of methyl 3-methoxy-1-methyl-1H-pyrazole-5-carboxylate(2.01 g, 11.8 mmol) in methanol (15 mL) was added 8N aqueous sodiumhydroxide solution (3.00 mL), and the mixture was stirred at roomtemperature for 18 hr. 6N Hydrochloric acid (4.00 mL) was added to themixture, and the mixture was concentrated under reduced pressure. Waterwas added to the residue, and the precipitate was collected byfiltration, washed with water and air-dried. The precipitate wassuspended in diisopropyl ether, and the mixture was stirred at 80° C.for 15 min. After allowing to cool to room temperature, the precipitatewas collected by filtration, washed with diisopropyl ether, and driedunder reduced pressure to give the title compound (746 mg, yield 40%) asa white solid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 3.77 (3H, s), 3.93 (3H, s), 6.20 (1H, s),13.37 (1H, br s).

Reference Example 59 Production of methyl3-ethoxy-1-methyl-1H-pyrazole-5-carboxylate

Using methyl 3-hydroxy-1-methyl-1H-pyrazole-5-carboxylate (2.34 g, 15.0mmol), iodoethane (3.51 g, 22.5 mmol), potassium carbonate (4.15 g, 30.0mmol) and N,N-dimethylformamide (15 mL), and in the same manner as inReference Example 57, the title compound (2.59 g, yield 94%) wasobtained.

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.28 (3H, t, J=7.0 Hz), 3.81 (3H, s), 3.93(3H, s), 4.10 (2H, q, J=7.0 Hz), 6.25 (1H, s).

Reference Example 60 Production of3-ethoxy-1-methyl-1H-pyrazole-5-carboxylic acid

Using methyl 3-ethoxy-1-methyl-1H-pyrazole-5-carboxylate (2.59 g, 14.1mmol), methanol (15 mL) and 8N aqueous sodium hydroxide solution (3.00mL), and in the same manner as in Reference Example 58, the titlecompound (1.94 g, yield 81%) was obtained.

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.28 (3H, t, J=7.0 Hz), 3.92 (3H, s), 4.09(2H, q, J=7.0 Hz), 6.19 (1H, s), 13.37 (1H, br s).

Reference Example 61 Production of methyl3-(2-methoxyethoxy)-1-methyl-1H-pyrazole-5-carboxylate

Using methyl 3-hydroxy-1-methyl-1H-pyrazole-5-carboxylate (2.34 g, 15.0mmol), 1-bromo-2-methoxyethane (3.13 g, 22.5 mmol), potassium carbonate(4.15 g, 30.0 mmol) and N,N-dimethylformamide (15 mL), and in the samemanner as in Reference Example 57, the title compound (3.03 g, yield94%) was obtained.

¹H-NMR (DMSO-d₆, 300 MHz) δ 3.28 (3H, s), 3.57-3.64 (2H, m), 3.81 (3H,s), 3.93 (3H, s), 4.14-4.20 (2H, m), 6.28 (1H, s).

Reference Example 62 Production of3-(2-methoxyethoxy)-1-methyl-1H-pyrazole-5-carboxylic acid

Using methyl 3-(2-methoxyethoxy)-1-methyl-1H-pyrazole-5-carboxylate(3.03 g, 14.1 mmol), methanol (15 mL) and 8N aqueous sodium hydroxidesolution (3.00 mL), and in the same manner as in Reference Example 58,the title compound (2.72 g, yield 96%) was obtained.

¹H-NMR (DMSO-d₆, 300 MHz) δ 3.28 (3H, s), 3.57-3.63 (2H, m), 3.92 (3H,s), 4.13-4.19 (2H, m), 6.21 (1H, s), 13.39 (1H, br s).

Example 1 Production ofN-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]tetrahydro-2H-pyran-4-carboxamide

A mixture of 6-iodoimidazo[1,2-b]pyridazin-2-amine (550 mg, 2.11 mmol),tetrahydro-2H-pyran-4-carbonyl chloride (320 mg, 2.15 mmol) andN,N-dimethylacetamide (5.0 mL) was stirred at room temperature for 3 hr.The reaction mixture was poured into water, and the precipitated solidwas collected by filtration, washed with water, and air-dried to giveN-(6-iodoimidazo[1,2-b]pyridazin-2-yl)tetrahydro-2H-pyran-4-carboxamideas a white powder.

A mixture ofN-(6-iodoimidazo[1,2-b]pyridazin-2-yl)tetrahydro-2H-pyran-4-carboxamide,3-aminophenol (436 mg, 4.0 mmol), potassium carbonate (552 mg, 4.0 mmol)and N,N-dimethylformamide (5.0 mL) was stirred with heating at 180° C.for 15 min using a microwave synthesizer. After cooling, the reactionmixture was filtrated, and the filtrate was purified by preparative HPLCto give the title compound (364 mg, 49%) as a dark brown powder.

¹H-NMR (CDCl₃, 400 MHz) δ 1.67-1.81 (4H, m), 2.34-2.44 (1H, m),3.25-3.34 (2H, m), 3.78 (2H, s), 3.86-3.94 (2H, m), 6.33-6.37 (1H, m),6.37-6.43 (2H, m), 6.67 (1H, d, J=9.5 Hz), 7.02 (1H, t, J=8.1 Hz), 7.54(1H, d, J=9.5 Hz), 7.89 (1H, s), 8.06 (1H, s).

In the same manner as in Example 1, the compounds of Examples 2 to 5were synthesized. The structures of the compounds of Examples 2 to 5 areshown in Table 1.

TABLE 1 Example MS No. Chemical structural formula (m/Z) 2

347 3

284 4

310 5

352

Example 6 Production ofN-(3-{[2-(acetylamino)imidazo[1,2-b]pyridazin-6-yl]oxy}phenyl)cyclopropanecarboxamide

A mixture of N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]acetamide(17 mg, 0.06 mmol), cyclopropanecarbonyl chloride (9.5 mg, 0.09 mmol)and N,N-dimethylacetamide (0.5 mL) was stirred at room temperature for14 hr. The reaction mixture was purified by preparative HPLC to give thetitle compound (10.8 mg, 51%).

LC-MS 352 (M+H).

In the same manner as in Example 6, the compounds of Examples 7 to 51were synthesized. The structures of the compounds of Examples 7 to 51are shown in Tables 2 to 7.

TABLE 2 Example MS No. Chemical structural formula (m/Z) 7

519 8

469 9

452 10

526 11

476 12

459 13

394 14

368

TABLE 3 Example MS No. Chemical structural formula (m/Z) 15

378 16

406 17

408 18

410 19

422 20

406 21

379 22

378

TABLE 4 Example MS No. Chemical structural formula (m/Z) 23

420 24

394 25

404 26

432 27

434 28

436 29

448 30

432

TABLE 5 Example MS No. Chemical structural formula (m/Z) 31

405 32

420 33

462 34

436 35

446 36

474 37

476 38

478

TABLE 6 Example MS No. Chemical structural formula (m/Z) 39

490 40

474 41

447 42

422 43

464 44

438 45

448 46

476

TABLE 7 Example MS No. Chemical structural formula (m/Z) 47

478 48

480 49

492 50

449 51

474

Example 52 Production ofN-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-2-fluoro-3-(trifluoromethyl)benzamide

UsingN-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(309 mg, 1.00 mmol), 2-fluoro-3-(trifluoromethyl)benzoic acid (312 mg,1.50 mmol), 1-hydroxybenzotriazole (203 mg, 1.50 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (288 mg,1.50 mmol) and N,N-dimethylformamide (5.0 mL) as starting materials andin the same manner as in Example 106, the title compound (380 mg, 76%)was obtained as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.78-0.82 (4H, m), 1.88-1.95 (1H, m),7.03-7.09 (2H, m), 7.45 (1H, t, J=8.1 Hz), 7.52-7.57 (2H, m), 7.66-7.67(1H, m), 7.94-8.07 (4H, m), 10.79 (1H, s), 11.09 (1H, s).

Example 53 Production ofN-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-3-fluoro-5-(trifluoromethyl)benzamide

UsingN-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(309 mg, 1.00 mmol), 3-fluoro-5-(trifluoromethyl)benzoic acid (312 mg,1.50 mmol), 1-hydroxybenzotriazole (203 mg, 1.50 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (288 mg,1.50 mmol) and N,N-dimethylformamide (5.0 mL) as starting materials andin the same manner as in Example 106, the title compound (437 mg, 88%)was obtained as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.79-0.82 (4H, m), 1.88-1.97 (1H, m),7.04-7.10 (2H, m), 7.47 (1H, t, J=8.4 Hz), 7.64-7.72 (2H, m), 7.96-8.15(5H, m), 10.63 (1H, s), 11.10 (1H, s).

Example 54 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-3-(trifluoromethyl)benzamide

UsingN-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(163 mg, 0.50 mmol), 3-(trifluoromethyl)benzoic acid (950 mg, 5.00mmol), 1-hydroxybenzotriazole (676 mg, 5.00 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (959 mg,5.00 mmol) and N,N-dimethylformamide (5.0 mL) as starting materials andin the same manner as in Example 106, the title compound (160 mg, 64%)was obtained as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.79-0.81 (4H, m), 1.88-1.95 (1H, m),7.08-7.25 (2H, m), 7.42 (1H, t, J=9.6 Hz), 7.60-7.79 (2H, m), 7.95-8.07(3H, m), 8.25-8.30 (2H, m), 10.51 (1H, s), 11.08 (1H, s).

Example 55 Production ofN-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-4-fluoro-3-(trifluoromethyl)benzamide

UsingN-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(309 mg, 1.00 mmol), 4-fluoro-3-(trifluoromethyl)benzoic acid (312 mg,1.50 mmol), 1-hydroxybenzotriazole (203 mg, 1.50 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (288 mg,1.50 mmol) and N,N-dimethylformamide (5.0 mL) as starting materials andin the same manner as in Example 106, the title compound (380 mg, 76%)was obtained as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.80-0.82 (4H, m), 1.88-1.96 (1H, m),7.02-7.10 (2H, m), 7.46 (1H, t, J=8.1 Hz), 7.63-7.74 (3H, m), 7.98 (1H,s), 8.06-8.36 (3H, m), 10.59 (1H, s), 11.10 (1H, s).

Example 56 Production ofN-[4-chloro-5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-3-(trifluoromethyl)benzamide

UsingN-[6-(3-amino-6-chloro-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(181 mg, 0.50 mmol), 3-(trifluoromethyl)benzoic acid (114 mg, 0.60mmol), 1-hydroxybenzotriazole (81 mg, 0.60 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (115 mg,0.60 mmol) and N,N-dimethylformamide (5.0 mL) as starting materials andin the same manner as in Example 106, the title compound (54 mg, 20%)was obtained as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.79-0.82 (4H, m), 1.88-1.94 (1H, m), 7.17(1H, d, J=9.6 Hz), 7.76-7.85 (3H, m), 7.92 (1H, s), 7.98-8.08 (2H, m),8.24-8.30 (2H, m), 10.60 (1H, s), 11.08 (1H, s).

Example 57 Production ofN-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-2-fluoro-5-(trifluoromethyl)benzamide

UsingN-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(309 mg, 1.00 mmol), 2-fluoro-5-(trifluoromethyl)benzoic acid (312 mg,1.50 mmol), 1-hydroxybenzotriazole (203 mg, 1.50 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (288 mg,1.50 mmol) and N,N-dimethylformamide (5.0 mL) as starting materials andin the same manner as in Example 106, the title compound (198 mg, 40%)was obtained as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.79-0.82 (4H, m), 1.88-1.94 (1H, m),7.02-7.09 (2H, m), 7.43-7.68 (4H, m), 7.98-8.09 (4H, m), 10.76 (1H, s),11.09 (1H, s).

Example 58 Production ofN-[2-chloro-5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-3-(trifluoromethyl)benzamide

A mixture ofN-[6-(3-amino-4-chlorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(103 mg, 0.30 mmol), 3-(trifluoromethyl)benzoyl chloride (75 mg, 0.36mmol) and N-methylpyrrolidone (3.0 mL) was heated to 50° C., and themixture was stirred for 10 min. The reaction mixture was poured intosaturated aqueous sodium hydrogencarbonate solution, and extracted withethyl acetate. The extract was dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography (hexane/ethylacetate=1/19→ethyl acetate) to give the title compound (131 mg, 85%) asa white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.78-0.82 (4H, m), 1.90-1.94 (1H, m), 7.10(1H, d, J=9.9 Hz), 7.27 (1H, dd, J=2.7 Hz, 8.7 Hz), 7.57 (1H, d, J=3.0Hz), 7.65 (1H, d, J=8.7 Hz), 7.80 (1H, d, J=7.8 Hz), 7.97-8.01 (2H, m),8.06 (1H, d, J=9.6 Hz), 8.26-8.31 (2H, m), 10.43 (1H, brs), 11.08 (1H,brs).

Example 59 Production ofN-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-2-(trifluoromethyl)isonicotinamide

UsingN-[6-(3-amino-4-chlorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(103 mg, 0.30 mmol), 2-(trifluoromethyl)isonicotinic acid (86 mg, 0.45mmol), 1-hydroxybenzotriazole (61 mg, 0.45 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (86 mg, 0.45mmol) and N,N-dimethylformamide (3.0 mL) as starting materials and inthe same manner as in Example 106, the title compound (102 mg, 71%) wasobtained as a light blue powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.78-0.81 (4H, m), 1.89-1.94 (1H, m),7.05-7.10 (2H, m), 7.48 (1H, t, J=8.1 Hz), 7.64-7.72 (2H, m), 7.98 (1H,s), 8.07-8.35 (3H, m), 8.99 (1H, d, J=5.1 Hz), 10.80 (1H, s), 11.09 (1H,s).

Example 60 Production ofN-[2-bromo-5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-3-(trifluoromethyl)benzamide

UsingN-[6-(3-amino-4-bromophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(178 mg, 0.46 mmol), 3-(trifluoromethyl)benzoyl chloride (92 mg, 0.44mmol), triethylamine (0.14 mL, 1.00 mmol) and tetrahydrofuran (5.0 mL)as starting materials and in the same manner as in Example 96, the titlecompound (67 mg, 24%) was obtained as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.79-0.82 (4H, m), 1.90-1.95 (1H, m),7.11-7.22 (2H, m), 7.54 (1H, d, J=2.7 Hz), 7.77-7.82 (2H, m), 7.97-8.08(3H, m), 8.26-8.31 (2H, m), 10.43 (1H, s), 11.09 (1H, s).

Example 61 Production of ethyl6-(3-aminophenoxy)imidazo[1,2-b]pyridazine-2-carboxylate

A mixture of ethyl 6-iodoimidazo[1,2-b]pyridazine-2-carboxylate (951 mg,3.00 mmol), 3-aminophenol (655 mg, 6.00 mmol), potassium carbonate (622mg, 4.50 mmol) and N,N-dimethylformamide (9.0 mL) was stirred at 150° C.for 6 hr. After allowing the reaction mixture to cool to roomtemperature, ethyl acetate and water were added to the mixture and theinsoluble material was filtered through celite. The organic layer wascollected from the filtrate, washed with saturated aqueous sodiumhydrogencarbonate solution, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography (ethylacetate/hexane=1/19→ethyl acetate alone) to give the title compound (350mg, 39%).

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.30 (3H, t, J=7.2 Hz), 4.29 (2H, q, J=7.2Hz), 5.34 (2H, brs), 6.35-6.48 (3H, m), 7.07 (1H, t, J=8.1 Hz), 7.17(1H, d, J=9.9 Hz), 8.20 (1H, d, J=9.6 Hz), 8.61 (1H, s).

Example 62 Production of ethyl6-(3-{[3-(trifluoromethyl)benzoyl]amino}phenoxy)imidazo[1,2-b]pyridazine-2-carboxylate

Using ethyl 6-(3-aminophenoxy)imidazo[1,2-b]pyridazine-2-carboxylate(350 mg, 1.17 mmol), 3-(trifluoromethyl)benzoic acid (342 mg, 1.80mmol), 1-hydroxybenzotriazole (243 mg, 1.80 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (345 mg,1.80 mmol) and N,N-dimethylformamide (5.0 mL) as starting materials andin the same manner as in Example 106, the title compound (496 mg, 90%)was obtained as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ1.29 (3H, t, J=7.1 Hz), 4.29 (2H, q, J=7.1Hz), 7.10 (1H, dd, J=1.5 Hz, 7.5 Hz), 7.29 (1H, d, J=9.9 Hz), 7.49 (1H,t, J=8.4 Hz), 7.68-7.82 (3H, m), 7.97-8.00 (1H, m), 8.25-8.28 (3H, m),8.62 (1H, s), 10.63 (1H, s).

Example 63 Production of6-(3-{[3-(trifluoromethyl)benzoyl]amino}phenoxy)imidazo[1,2-b]pyridazine-2-carboxylicacid

A mixture of ethyl6-(3-{[3-(trifluoromethyl)benzoyl]amino}phenoxy)imidazo[1,2-b]pyridazine-2-carboxylate(470 mg, 1.00 mmol), 8N aqueous sodium hydroxide solution (2.0 mL) andmethanol (6.0 mL) was stirred at room temperature for 4 hr. 6NHydrochloric acid (2.7 mL) and water (25 mL) were added to the mixture,and the mixture was extracted with ethyl acetate (50 mL). The extractwas dried over anhydrous magnesium sulfate, and the solvent wasevaporated under reduced pressure to give the title compound (425 mg,96%) as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 7.10 (1H, dd, J=2.1 Hz, 7.8 Hz), 7.27 (1H,d, J=9.9 Hz), 7.48 (1H, t, J=7.8 Hz), 7.69-7.82 (3H, m), 7.98 (1H, d,J=7.5 Hz), 8.23-8.29 (3H, m), 8.52 (1H, s), 10.62 (1H, s), 12.85 (1H,brs).

Example 64 Production of tert-butyl[6-(3-{[3-(trifluoromethyl)benzoyl]amino}phenoxy)imidazo[1,2-b]pyridazin-2-yl]carbamate

A suspension of6-(3-{[3-(trifluoromethyl)benzoyl]amino}phenoxy)imidazo[1,2-b]pyridazine-2-carboxylicacid (111 mg, 0.25 mmol), diphenylphosphoryl azide (103 mg, 0.375 mmol),triethylamine (51 mg, 0.5 mmol) and tert-butanol (5.0 mL) was stirred atroom temperature for 5 min, heated to 100° C. and stirred overnight.After allowing the reaction mixture to cool to room temperature, ethylacetate was added to the mixture, and the mixture was washed withsaturated aqueous sodium hydrogencarbonate solution, dried overanhydrous magnesium sulfate, and filtrated. The solvent was evaporatedunder reduced pressure, and the residue was purified by silica gelcolumn chromatography (ethyl acetate/hexane=1/19→ethyl acetate alone) togive the title compound (79 mg, 39%) as a white solid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.47 (9H, s), 7.00-7.05 (2H, m), 7.45 (1H,t, J=8.1 Hz), 7.65-7.81 (4H, m), 7.96-8.03 (2H, m), 8.24-8.28 (2H, m),10.04 (1H, brs), 10.58 (1H, brs).

Example 65 Production of6-(3-{[3-(1-cyano-1-methylethyl)benzoyl]amino}phenoxy)imidazo[1,2-b]pyridazine-2-carboxylicacid

To a mixture of 3-(1-cyano-1-methylethyl)benzoic acid (454 mg, 2.40mmol), tetrahydrofuran (10 mL) and N,N-dimethylformamide (0.01 mL) wasadded oxalyl chloride (366 mg, 2.88 mmol), and the mixture was stirredat room temperature for 2 hr. The solvent was evaporated under reducedpressure, tetrahydrofuran was added to the residue, and the mixture wasazeotroped twice. The residue was dissolved in N-methylpyrrolidone (4mL), added to a solution of ethyl6-(3-aminophenoxy)imidazo[1,2-b]pyridazine-2-carboxylate (350 mg, 1.17mmol) in N-methylpyrrolidone (6 mL), and the mixture was stirred at roomtemperature for 2 hr. Ethyl acetate was added to the reaction mixture,and the mixture was washed with saturated aqueous sodiumhydrogencarbonate solution, dried over anhydrous magnesium sulfate, andfiltrated. To the residue were added 8N aqueous sodium hydroxidesolution (4.0 mL) and methanol (10.0 mL), and the mixture was stirred atroom temperature for 10 min. 6N Hydrochloric acid (5.0 mL) and water (60mL) were added to the mixture, and the mixture was extracted with ethylacetate (150 mL). The extract was dried over anhydrous magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theresidue was washed with hexane to give the title compound (828 mg, 94%)as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ1.75 (6H, s), 7.08 (1H, dd, J=1.5 Hz, 8.4Hz), 7.27 (1H, d, J=9.6 Hz), 7.47 (1H, t, J=7.8 Hz), 7.60-7.77 (4H, m),7.92-8.03 (2H, m), 8.24 (1H, d, J=10.2 Hz), 8.52 (1H, s), 10.46 (1H, s),12.81 (1H, brs).

Example 66 Production of tert-butyl[6-(3-{[3-(1-cyano-1-methylethyl)benzoyl]amino}phenoxy)imidazo[1,2-b]pyridazin-2-yl]carbamate

Using6-(3-{[3-(1-cyano-1-methylethyl)benzoyl]amino}phenoxy)imidazo[1,2-b]pyridazine-2-carboxylicacid (826 mg, 1.87 mmol), diphenylphosphoryl azide (771 mg, 2.81 mmol),triethylamine (381 mg, 3.74 mmol) and tert-butanol (30.0 mL), and in thesame manner as in Example 64, the title compound (682 mg, 71%) wasobtained as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.47 (9H, s), 1.74 (6H, s), 6.99-7.05 (2H,m), 7.44 (1H, t, J=8.4 Hz), 7.57-7.77 (5H, m), 7.91-7.94 (1H, m),8.00-8.03 (2H, m), 10.04 (1H, brs), 10.43 (1H, s).

Example 67 Production ofN-[6-(4-amino-3-nitrophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide

A mixture ofN-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (656 mg,2.00 mmol), 4-amino-3-nitrophenol (616 mg, 4.00 mmol), potassiumcarbonate (411 mg, 3.00 mmol) and N,N-dimethylformamide (6.0 mL) wasstirred at 150° C. for 3 hr. After allowing the reaction mixture to coolto room temperature, ethyl acetate (100 mL), tetrahydrofuran (40 mL) andwater (40 mL) were added to the mixture, and the insoluble material wasfiltered through celite. The organic layer was collected from thefiltrate, washed with saturated aqueous sodium hydrogencarbonatesolution, dried over anhydrous magnesium sulfate, and filtrated.Dichloromethane (20 mL) was added to the residue, and the precipitatewas collected by filtration to give the title compound (367 mg, 52%).The filtrate was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography (ethylacetate/hexane=1/19→ethyl acetate alone) to give the title compound (125mg, 18%) as a white solid.

¹H-NMR (DMSO-d₆, 300 MHz) δ0.78-0.81 (4H, m), 1.84-1.91 (1H, m), 7.04(1H, d, J=9.3 Hz), 7.11 (1H, d, J=9.3 Hz), 7.44 (1H, dd, J=3.0 Hz, 9.3Hz), 7.51 (2H, m), 7.83 (1H, d, J=2.4 Hz), 7.91 (1H, s), 8.01 (1H, d,J=9.3 Hz), 11.04 (1H, s).

Example 68 Production ofN-{6-[(2-{[[4-(trifluoromethyl)phenyl]amino}-1H-benzimidazol-6-yl)oxy]imidazo[1,2-b]pyridazin-2-yl}cyclopropanecarboxamide

A suspension ofN-[6-(4-amino-3-nitrophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(499 mg, 1.38 mmol), 10% palladium carbon (100 mg) and methanol (20.0mL) was stirred under a hydrogen atmosphere (up to 1 atm) at roomtemperature overnight. The insoluble material was filtered throughcelite, and the filtrate was evaporated under reduced pressure. Theresidue was dissolved in methanol (10 mL),4-(trifluoromethyl)phenylisothiocyanate (120 mg, 0.59 mmol) was added tothe mixture, and the mixture was stirred at room temperature for 1 hr.Iron (III) chloride (177 mg, 1.1 mmol) was added to the reactionmixture, and the mixture was further stirred at room temperature for 1.5hr. Ethyl acetate was added to the reaction mixture, and the mixture waswashed with saturated aqueous sodium hydrogencarbonate solution, driedover anhydrous magnesium sulfate, and filtrated. Dichloromethane (20 mL)was added to the residue, and the precipitate was collected byfiltration to give the title compound (367 mg, 52%). The filtrate wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography (ethyl acetate alone→ethylacetate/methanol=9:1). Ethyl acetate was added to the obtained oilysubstance, and the precipitate was collected by filtration to give thetitle compound (116 mg, 32%) as a pale-yellow solid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.78-0.81 (4H, m), 1.88-1.94 (1H, m),6.90-7.02 (2H, m), 7.22-7.39 (2H, m), 7.65-8.01 (6H, m), 9.98 (1H, d,J=8.1 Hz), 11.03 (1H, s), 11.20 (1H, d, J=16.2 Hz).

Example 69 Production ofN-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide

A mixture of tert-butyl[6-(3-{[3-(trifluoromethyl)benzoyl]amino}phenoxy)imidazo[1,2-b]pyridazin-2-yl]carbamate(2.37 g, 4.62 mmol), 4N hydrochloric acid-ethyl acetate solution (50 mL)and methanol (50 mL) was stirred at room temperature for 6 hr. Thesolvent was evaporated under reduced pressure, saturated aqueous sodiumhydrogencarbonate solution was added to the residue, and the mixture wasextracted with ethyl acetate. The extract was dried over anhydrousmagnesium sulfate and evaporated under reduced pressure, and the residuewas purified by silica gel column chromatography (ethyl acetatealone→ethyl acetate/methanol=4:1) to give the title compound (1.57 g,82%) as a green solid.

¹H-NMR (DMSO-d₆, 300 MHz) δ5.33 (2H, brs), 6.80 (1H, d, J=9.0 Hz), 6.94(1H, m), 7.15 (1H, s), 7.42 (1H, t, J=7.8 Hz), 7.63-7.80 (4H, m), 7.97(1H, d, J=7.5 Hz), 8.23-8.27 (2H, m), 10.54 (1H, s).

Example 70 Production ofN-{3-[(2-{[2-(methylamino)pyrimidin-4-yl]amino}imidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide

A mixture ofN-[3-({2-[(2-chloropyrimidin-4-yl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-3-(trifluoromethyl)benzamide(122 mg, 0.23 mmol), 2M methylamine-tetrahydrofuran solution (3.0 mL)and ethanol (6.0 mL) was heated to 70° C., and the mixture was stirredovernight. Ethyl acetate was added to the reaction mixture, and themixture was washed with saturated aqueous sodium hydrogencarbonatesolution, dried over anhydrous magnesium sulfate, and filtrated, and theresidue was purified by silica gel column chromatography (ethyl acetatealone→ethyl acetate/methanol=4:1). The obtained residue was washed withethyl acetate-hexane to give the title compound (60 mg, 50%) as a yellowsolid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 2.76 (3H, m), 6.15 (1H, d, J=5.1 Hz), 6.85(1H, m), 7.04-7.07 (2H, m), 7.47 (1H, t, J=8.1 Hz), 7.68-8.02 (6H, m),8.24-8.28 (2H, m), 8.44 (1H, m), 9.96 (1H, brs), 10.59 (1H, s).

Example 71 Production ofN-[3-({2-[(2-chloropyrimidin-4-yl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-3-(trifluoromethyl)benzamide

To a solution ofN-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide(103 mg, 0.25 mmol) in tetrahydrofuran (15 mL) was added sodium hydride(60% in oil, 80 mg, 2.0 mmol), and the mixture was stirred at roomtemperature for 10 min. 2,4-Dichloropyrimidine (149 mg, 1.00 mmol) wasadded to the reaction mixture, and the mixture was heated to 60° C.After 1 hr, the reaction mixture was cooled to room temperature andethyl acetate was added thereto. The mixture was washed with saturatedaqueous sodium hydrogencarbonate solution, dried over anhydrousmagnesium sulfate, and filtrated. The residue was purified by silica gelcolumn chromatography (ethyl acetate/hexane=1/19→ethyl acetate alone)and the obtained solid was washed with ethyl acetate/hexane (=1/2) togive the title compound (27 mg, 21%) as a light blue solid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 6.97-7.17 (3H, m), 7.48 (1H, t, J=8.1 Hz),7.68-8.00 (4H, m), 8.08-8.29 (5H, m), 10.61 (1H, brs), 10.93 (1H, brs).

Example 72 Production ofN-(3-{[2-(1,3-thiazol-2-ylamino)imidazo[1,2-b]pyridazin-6-yl]oxy}phenyl)-3-(trifluoromethyl)benzamide

A mixture ofN-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide(165 mg, 0.4 mmol), tris(dibenzylideneacetone)dipalladium (0) (37 mg,0.04 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine)(46 mg, 0.03 mmol), sodium t-butoxide (77 mg, 0.8 mmol), 2-bromothiazole(98 mg, 0.6 mmol) and N,N-dimethylacetamide (2 mL) was heated to 70° C.under nitrogen atmosphere, and the mixture was stirred for 2 hr. Afterallowing the reaction mixture to cool to room temperature, ethyl acetatewas added to the mixture, and the mixture was washed with saturatedaqueous sodium hydrogencarbonate solution, dried over anhydrousmagnesium sulfate, and filtrated. The residue was purified by silica gelcolumn chromatography (ethyl acetate/hexane=1/19→ethyl acetate alone) togive the title compound (10 mg, 5%) as a light blue solid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 6.92-7.27 (4H, m), 7.46 (1H, t, J=7.8 Hz),7.67-8.06 (6H, m), 8.24-8.28 (2H, m), 10.58 (1H, brs), 10.90 (1H, brs).

Example 73 Production ofN-(3-{[2-(hydroxymethyl)imidazo[1,2-b]pyridazin-6-yl]oxy}phenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide

To a solution of (6-iodoimidazo[1,2-b]pyridazin-2-yl)methanol (400 mg,1.45 mmol) in N,N-dimethylformamide (4.0 mL) were addedN-(3-hydroxyphenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide (504 mg, 2.18mmol) and potassium carbonate (402 mg, 2.91 mmol), and the mixture wasstirred at 150° C. for 16 hr. After cooling the mixture to roomtemperature, water was added to the reaction mixture, and the mixturewas extracted with ethyl acetate/tetrahydrofuran, washed with saturatedbrine, dried over anhydrous sodium sulfate, and filtrated. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography (ethyl acetate/ethanol=100/0→10/1) togive the title compound (70 mg, 13%) as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 2.19 (3H, s), 3.98 (3H, s), 4.55 (1H, d,J=5.4 Hz), 5.19 (1H, d, J=5.4 Hz), 6.82 (1H, s), 6.98-7.03 (1H, m), 7.08(1H, d, J=9.6 Hz), 7.39-7.46 (1H, m), 7.59-7.63 (1H, m), 7.66-7.68 (1H,m), 7.88 (1H, s), 8.10 (1H, d, J=9.6 Hz), 10.23 (1H, s).

Example 74 Production ofN-[4-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-5-methyl-1-phenyl-1H-pyrazole-3-carboxamide

Using 5-methyl-1-phenyl-1H-pyrazole-3-carboxylic acid (196 mg, 0.97mmol), tetrahydrofuran (2.0 mL), N,N-dimethylformamide (30 μL, 0.39mmol), oxalyl chloride (85 μL, 0.97 mmol),N-[6-(4-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(200 mg, 0.65 mmol) and N,N-dimethylacetamide (4.0 mL), and in the samemanner as in Example 255, the title compound (223 mg, 70%) was obtainedas a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.76-0.83 (4H, m), 1.86-1.96 (1H, m), 2.31(3H, s), 6.85 (1H, s), 7.02 (1H, d, J=9.6 Hz), 7.23 (2H, d, J=9.3 Hz),7.36-7.46 (5H, m), 7.71 (2H, J=9.3 Hz), 7.92 (1H, s), 8.01 (1H, d, J=9.6Hz), 10.62 (1H, s), 11.05 (1H, s).

Example 75 Production ofN-[4-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-3-methyl-1-phenyl-1H-pyrazole-5-carboxamide

Using 3-methyl-1-phenyl-1H-pyrazole-5-carboxylic acid (196 mg, 0.97mmol), tetrahydrofuran (2.0 mL), N,N-dimethylformamide (30 μL, 0.39mmol), oxalyl chloride (85 μL, 0.97 mmol),N-[6-(4-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(200 mg, 0.65 mmol) and N,N-dimethylacetamide (4.0 mL), and in the samemanner as in Example 255, the title compound (209 mg, 65%) was obtainedas a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.77-0.83 (4H, m), 1.86-1.96 (1H, m), 2.36(3H, s), 6.80 (1H, s), 7.03 (1H, d, J=9.5 Hz), 7.21-7.25 (2H, m),7.48-7.67 (5H, m), 7.86-7.91 (2H, m), 7.92 (1H, s), 8.01 (1H, d, J=9.5Hz), 10.18 (1H, s), 11.05 (1H, s).

Example 76 Production of1-benzyl-N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-1H-pyrrole-3-carboxamide

Using 1-benzyl-1H-pyrrole-3-carboxylic acid (276 mg, 1.37 mmol),tetrahydrofuran (3.0 mL), N,N-dimethylformamide (20 μL, 0.26 mmol),oxalyl chloride (120 μL, 1.37 mmol),N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]-2-methylcyclopropanecarboxamide(300 mg, 0.92 mmol) and N,N-dimethylacetamide (6.0 mL), and in the samemanner as in Example 249, the title compound (114 mg, 24%) was obtainedas a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.77-0.83 (4H, m), 1.85-1.96 (1H, m), 5.15(2H, s), 6.62-6.64 (1H, m), 6.88-6.92 (1H, m), 7.05 (1H, d, J=9.6 Hz),7.07-7.12 (1H, m), 7.23-7.62 (6H, m), 7.56-7.62 (2H, m), 7.93 (1H, s),8.03 (1H, d, J=9.6 Hz), 9.43 (1H, s), 11.07 (1H, s).

Example 77 Production ofN-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-3-methyl-1-phenyl-1H-pyrazole-5-carboxamide

Using 3-methyl-1-phenyl-1H-pyrazole-5-carboxylic acid (294 mg, 1.45mmol), tetrahydrofuran (3.0 mL), N,N-dimethylformamide (30 μL, 0.39mmol), oxalyl chloride (127 μL, 1.45 mmol),N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(300 mg, 0.97 mmol) and N,N-dimethylacetamide (6.0 mL), and in the samemanner as in Example 255, the title compound (342 mg, 71%) was obtainedas a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.75-0.86 (4H, m), 1.85-1.95 (1H, m), 2.34(3H, s), 6.78 (1H, s), 6.92-6.98 (1H, m), 7.05 (1H, d, J=9.9 Hz),7.33-7.43 (1H, m), 7.46-7.66 (5H, m), 7.69-7.78 (2H, m), 7.97 (1H, s),8.04 (1H, d, J=9.9 Hz), 10.21 (1H, s), 11.08 (1H, s).

Example 78 Production ofN-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-5-methyl-1-phenyl-1H-pyrazole-3-carboxamide

Using 5-methyl-1-phenyl-1H-pyrazole-3-carboxylic acid (294 mg, 1.45mmol), tetrahydrofuran (3.0 mL), N,N-dimethylformamide (30 μL, 0.39mmol), oxalyl chloride (127 μL, 1.45 mmol),N-[6-(4-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(300 mg, 0.97 mmol) and N,N-dimethylacetamide (6.0 mL), and in the samemanner as in Example 255, the title compound (317 mg, 66%) was obtainedas a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.76-0.84 (4H, m), 1.84-1.96 (1H, m), 2.29(3H, s), 6.85 (1H, s), 6.96-7.01 (1H, m), 7.04 (1H, d, J=9.6 Hz),7.30-7.58 (8H, m), 7.95 (1H, s), 8.03 (1H, d, J=9.6 Hz), 10.64 (1H, s),11.08 (1H, s).

Example 79 Production ofN-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}thio)phenyl]-3-methyl-1-phenyl-1H-pyrazole-5-carboxamide

Using 3-methyl-1-phenyl-1H-pyrazole-5-carboxylic acid (186 mg, 0.92mmol), tetrahydrofuran (2.0 mL), N,N-dimethylformamide (30 μL, 0.39mmol), oxalyl chloride (80 μL, 0.92 mmol),N-{6-[(3-aminophenyl)thio]imidazo[1,2-b]pyridazin-2-yl}cyclopropanecarboxamide(200 mg, 0.61 mmol) and N,N-dimethylacetamide (4.0 mL), and in the samemanner as in Example 255, the title compound (203 mg, 65%) was obtainedas a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.78-0.84 (4H, m), 1.86-1.96 (1H, m), 2.35(3H, s), 6.78 (1H, s), 6.89-6.94 (1H, m), 7.27-7.31 (1H, m), 7.40-7.65(7H, m), 7.86-7.95 (2H, m), 8.09-8.24 (1H, m), 10.25 (1H, s), 11.17 (1H,s).

Example 80 Production ofN-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}thio)phenyl]-5-methyl-1-phenyl-1H-pyrazole-3-carboxamide

Using 5-methyl-1-phenyl-1H-pyrazole-3-carboxylic acid (196 mg, 0.97mmol), tetrahydrofuran (2.0 mL), N,N-dimethylformamide (30 μL, 0.39mmol), oxalyl chloride (80 μL, 0.92 mmol),N-{6-[(3-aminophenyl)thio]imidazo[1,2-b]pyridazin-2-yl}cyclopropanecarboxamide(200 mg, 0.61 mmol) and N,N-dimethylacetamide (4.0 mL), and in the samemanner as in Example 255, the title compound (155 mg, 49%) was obtainedas a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.78-0.86 (4H, m), 1.85-1.96 (1H, m), 2.29(3H, s), 6.86 (1H, s), 6.94 (1H, d, J=9.3 Hz), 7.29-7.46 (7H, m),7.71-7.76 (1H, m), 7.87 (1H, s), 7.88 (1H, d, J=9.3 Hz), 8.12 (1H, s),10.63 (1H, s), 11.16 (1H, s).

Example 81 Production ofN-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]-2-methylcyclopropanecarboxamide

Using 3-amino-4-methylphenol (1.08 g, 8.77 mmol), N,N-dimethylformamide(30.0 mL), potassium tert-butoxide (1.02 g, 9.13 mmol),N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)-2-methylcyclopropanecarboxamide(2.5 g, 7.31 mmol) and potassium carbonate (0.51 g, 3.65 mmol), and inthe same manner as in Example 216, the title compound (1.38 g, 56%) wasobtained as a brown powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.61-0.69 (1H, m), 0.96-1.05 (1H, m),1.06-1.09 (3H, m), 1.19-1.27 (1H, m), 1.63-1.72 (1H, m), 2.04 (3H, s),5.05 (2H, s), 6.27 (1H, dd, J=8.0, 2.4 Hz), 6.41 (1H, d, J=2.4 Hz), 6.92(1H, d, J=9.5 Hz), 6.94 (1H, d, J=8.0 Hz), 7.94 (1H, s), 7.96 (1H, d,J=9.5 Hz), 10.96 (1H, s).

Example 82 Production ofN-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]-2-methylcyclopropanecarboxamide

To a solution of 3-amino-4-fluorophenol (0.42 g, 3.29 mmol) inN,N-dimethylformamide (9.0 mL) were addedN-(6-iodoimidazo[1,2-b]pyridazin-2-yl)-2-methylcyclopropanecarboxamide(0.75 g, 2.19 mmol) and potassium carbonate (0.61 g, 4.38 mmol), and themixture was stirred at 140° C. for 16 hr. Saturated brine was added tothe reaction mixture, and the mixture was extracted with ethylacetate/tetrahydrofuran, washed with saturated brine, dried overanhydrous sodium sulfate, and filtrated. The solvent was evaporatedunder reduced pressure, and the residue was purified by silica gelcolumn chromatography (ethyl acetate alone), and the obtained residuewas washed with hexane/ethyl acetate and filtrated to give the titlecompound (0.63 g, 88%) as a brown powder.

1H-NMR (DMSO-d₆, 300 MHz) δ 0.62-0.74 (1H, m), 0.96-1.04 (1H, m),1.07-1.09 (3H, m), 1.17-1.28 (1H, m), 1.62-1.72 (1H, m), 5.36 (2H, s),6.30-6.36 (1H, m), 6.57 (1H, dd, J=7.8, 2.7 Hz), 6.96 (1H, d, J=9.6 Hz),7.02 (1H, dd, J=11.4, 8.7 Hz), 7.94 (1H, s), 7.96-8.00 (1H, m), 10.97(1H, s).

Example 83 Production ofN-[6-(3-amino-4-chlorophenoxy)imidazo[1,2-b]pyridazin-2-yl]-2-methylcyclopropanecarboxamide

Using 3-amino-4-chlorophenol (1.57 g, 11.0 mmol), N,N-dimethylformamide(25.0 mL),N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)-2-methylcyclopropanecarboxamide(2.50 g, 7.31 mmol) and potassium carbonate (2.02 g, 14.6 mmol), and inthe same manner as in Example 82, the title compound (1.92 g, 73%) wasobtained as a brown powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.61-0.72 (1H, m), 0.97-1.04 (1H, m),1.07-1.12 (3H, m), 1.17-1.28 (1H, m), 1.63-1.73 (1H, m), 5.54 (2H, s),6.39 (1H, dd, J=8.6, 2.9 Hz), 6.60 (1H, d, J=2.9 Hz), 6.99 (1H, d, J=9.5Hz), 7.22 (1H, dd, J=8.6 Hz), 7.96 (1H, s), 8.00 (1H, d, J=8.6 Hz),10.98 (1H, s).

Example 84 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]-4-methyl-2-oxo-2,3-dihydro-1,3-oxazole-5-carboxamide

In the same manner as in Example 259 and using4-methyl-2-oxo-2,3-dihydro-1,3-oxazole-5-carboxylic acid (159 mg, 1.1mmol), tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalylchloride (382 μL, 4.44 mmol),N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(300 mg, 0.93 mmol) and N,N-dimethylacetamide (7 mL) as startingmaterials, the title compound (145 mg, 35%) was obtained as a whitesolid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.76-0.84 (4H, m), 1.86-1.97 (1H, m), 2.22(3H, s), 2.27 (3H, s), 6.98-7.09 (2H, m), 7.24-7.33 (2H, m), 7.94 (1H,s), 8.02 (1H, d, J=9.6 Hz), 9.41 (1H, s), 11.07 (1H, s), 11.46 (1H,brs).

Example 85 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]-1,5-dimethyl-1H-pyrazole-3-carboxamide

In the same manner as in Example 259 and using1,5-dimethyl-1H-pyrazole-3-carboxylic acid (145 mg, 1.0 mmol),tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride(320 μL, 4.44 mmol),N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(250 mg, 0.77 mmol) and N,N-dimethylacetamide (7 mL) as startingmaterials, the title compound (57 mg, 17%) was obtained as a whitesolid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.76-0.86 (4H, m), 1.87-1.97 (1H, m), 2.27(3H, s), 2.30 (3H, s), 3.83 (3H, s), 6.53 (1H, s), 6.97-7.06 (2H, m),7.25-7.34 (1H, m), 7.61 (1H, d, J=2.3 Hz), 7.92-7.97 (1H, m), 8.02 (1H,d, J=9.5 Hz), 9.35 (1H, s), 11.07 (1H, s).

Example 86 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]-1,3-dimethyl-4,5-dihydro-1H-pyrazole-5-carboxamide

In the same manner as in Example 278 and using1,3-dimethyl-4,5-dihydro-1H-pyrazole-5-carboxylic acid (120 mg, 0.87mmol),N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(200 mg, 0.62 mmol),O-(7-azabenzotriazol-1-yl)-N,N′,N′-tetramethyluroniumhexafluorophosphate (330 mg, 0.87 mmol), N,N-diisopropylethylamine (240mg, 1.8 mmol) and N,N-dimethylformamide (7 mL) as starting materials,the title compound (199 mg, 72%) was obtained as a white solid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.72-0.86 (4H, m), 1.87 (3H, s), 1.89-1.97(1H, m), 2.23 (3H, s), 2.74 (3H, s), 2.77-2.87 (1H, m), 2.98-3.13 (1H,m), 3.57 (1H, m), 6.95-7.07 (2H, m), 7.30 (1H, d, J=8.3 Hz), 7.51 (1H,d, J=2.3 Hz), 7.92 (1H, s), 8.02 (1H, d, J=9.8 Hz), 9.43 (1H, s), 11.07(1H, s).

Example 87 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazol[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-1,3-dimethyl-4,5-dihydro-1H-pyrazole-5-carboxamide

In the same manner as in Example 278 and using1,3-dimethyl-4,5-dihydro-1H-pyrazole-5-carboxylic acid (170 mg, 1.2mmol),N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(280 mg, 0.84 mmol),O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (450 mg, 1.2 mmol), N,N-diisopropylethylamine (330mg, 2.5 mmol) and N,N-dimethylformamide (7 mL) as starting materials,the title compound (240 mg, 63%) was obtained as a white solid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.75-0.84 (4H, m), 1.86 (3H, s), 1.89-1.96(1H, m), 2.71 (3H, s), 2.81 (1H, dd, J=17.4, 12.9 Hz), 2.98-3.11 (1H,m), 3.59-3.71 (1H, m), 7.06 (1H, d, J=9.5 Hz), 7.09-7.14 (1H, m), 7.38(1H, dd, J=10.4, 8.9 Hz), 7.87 (1H, dd, J=6.4, 3.0 Hz), 7.93 (1H, s),8.04 (1H, d, J=9.5 Hz), 9.75 (1H, s), 11.08 (1H, s).

Example 88 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]-1,4-dimethyl-4,5-dihydro-1H-pyrazole-3-carboxamide

A mixture ofN-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (300 mg,0.91 mmol),N-(5-hydroxy-2-methylphenyl)-1,4-dimethyl-4,5-dihydro-1H-pyrazole-3-carboxamide(290 mg, 1.2 mmol), cesium carbonate (600 mg, 1.8 mmol) and dimethylsulfoxide (2 mL) was stirred at 100° C. for 6 hr. Ethylacetate/tetrahydrofuran and water were added to the reaction mixture,and the aqueous layer was extracted with ethyl acetate/tetrahydrofuran(×4). Combined organic layer was washed with saturated brine, dried overanhydrous sodium sulfate, and filtrated. The filtrate was concentratedunder reduced pressure, and the residue was purified by silica gelcolumn chromatography (ethyl acetate/hexane=40/60→100/0) to give thetitle compound (300 mg, 73%) as a white solid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.75-0.85 (4H, m), 1.14 (3H, d, J=6.4 Hz),1.86-1.97 (1H, m), 2.23 (3H, s), 2.92 (3H, s), 3.05-3.12 (1H, m),3.22-3.32 (2H, m), 6.98 (1H, dd, J=8.3, 2.7 Hz), 7.03 (1H, d, J=9.8 Hz),7.28 (1H, d, J=8.3 Hz), 7.53 (1H, d, J=2.7 Hz), 7.94 (1H, s), 8.02 (1H,d, J=9.8 Hz), 9.18 (1H, s), 11.08 (1H, s).

Example 89 Production of3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)benzoicacid

A mixture ofN-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (518 mg,1.58 mmol), methyl 3-hydroxybenzoate (360 mg, 2.37 mmol), potassiumcarbonate (654 mg, 4.73 mmol) and N,N-dimethylformamide (4.0 mL) wasstirred at 110° C. for 2 days. The solvent was evaporated under reducedpressure, ethyl acetate, tetrahydrofuran and water were added to theresidue, and the aqueous layer was extracted three times with ethylacetate/tetrahydrofuran. Combined organic layer was washed withsaturated brine, dried over anhydrous sodium sulfate, and filtrated. Thesolvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography (ethylacetate/hexane=20/80→85/15) to give methyl3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)benzoate(225 mg, 41%) as a white powder.

To a solution of methyl3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)benzoate(225 mg, 0.64 mmol) in tetrahydrofuran (5.0 mL) was added 1N sodiumhydroxide (2.5 mL), and the mixture was stirred at room temperature for24 hr. 1N Hydrochloric acid was added to the mixture (pH=3), and theaqueous layer was extracted three times with ethylacetate/tetrahydrofuran. Combined organic layer was washed withsaturated brine, dried over anhydrous sodium sulfate, and filtrated. Thesolvent was evaporated under reduced pressure, and the residue wasfiltrated, and washed with ethyl acetate/hexane to give the titlecompound (150 mg, 69%) as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.71-0.89 (4H, m), 1.84-2.01 (1H, m), 7.09(1H, d, J=9.5 Hz), 7.48-7.68 (2H, m), 7.73 (1H, s), 7.84 (1H, d, J=7.2Hz), 7.94 (1H, s), 8.06 (1H, d, J=9.5 Hz), 11.08 (1H, s), 13.20 (1H,brs).

Example 90 Production ofN-[6-(5-amino-2-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide

To a suspension of sodium hydride (56 mg, 1.40 mmol) inN,N-dimethylformamide (2.0 mL) was added a solution of5-amino-2-methylphenol (173 mg, 1.40 mmol) in N,N-dimethylformamide (1.0mL), and the mixture was stirred at 0° C. for 30 min. To the reactionmixture was added a solution ofN-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (306 mg,0.933 mmol) in N,N-dimethylformamide (1.5 mL), and the mixture wasstirred at 110° C. for 24 hr. The solvent was evaporated under reducedpressure, and ethyl acetate and water were added to the residue. Theaqueous layer was extracted three times with ethyl acetate. Combinedorganic layer was washed with saturated brine, dried over anhydroussodium sulfate, and filtrated. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography (ethyl acetate/hexane=17/83→90/10) to give the titlecompound (94 mg, 31%) as a brown powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.73-0.89 (4H, m), 1.84-2.01 (1H, m), 1.97(3H, s), 5.08 (2H, s), 6.30 (1H, d, J=2.3 Hz), 6.40 (1H, dd, J=8.0, 2.3Hz), 6.94 (1H, d, J=8.0 Hz), 6.95 (1H, d, J=9.5 Hz), 7.93 (1H, s), 7.99(1H, d, J=9.5 Hz), 11.06 (1H, s).

Example 91 Production ofN-[6-(3-amino-4-chlorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide

A mixture ofN-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (800 mg,2.44 mmol), 3-amino-4-chlorophenol (422 mg, 2.93 mmol), potassiumcarbonate (843 mg, 6.10 mmol) and N,N-dimethylformamide (6.0 mL) wasstirred using a microwave synthesizer at 180° C. for 30 min. The solventwas evaporated under reduced pressure, ethyl acetate, tetrahydrofuranand water were added to the residue, and the aqueous layer was extractedthree times with ethyl acetate/tetrahydrofuran. Combined organic layerwas washed with saturated brine, dried over anhydrous sodium sulfate,and filtrated. The solvent was evaporated under reduced pressure, andthe residue was purified by silica gel column chromatography (ethylacetate/hexane=17/83→75/25) to give the title compound (610 mg, 73%) asa brown powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.72-0.87 (4H, m), 1.84-1.98 (1H, m), 5.56(2H, s), 6.40 (1H, dd, J=8.5, 2.8 Hz), 6.61 (1H, d, J=2.8 Hz), 7.00 (1H,d, J=9.8 Hz), 7.23 (1H, d, J=8.5 Hz), 7.98 (1H, s), 8.02 (1H, d, J=9.8Hz), 11.09 (1H, s).

Example 92 Production ofN-[6-(5-amino-2-chlorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide

Using N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (800mg, 2.44 mmol), 5-amino-2-chlorophenol (422 mg, 2.93 mmol), potassiumcarbonate (843 mg, 6.1 mmol) and N,N-dimethylformamide (6.0 mL) asstarting materials and in the same manner as in Example 91, the titlecompound (226 mg, 27%) was obtained as a brown solid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.73-0.86 (4H, m), 1.85-1.98 (1H, m), 5.47(2H, s), 6.47-6.51 (1H, m), 6.51 (1H, s), 7.04 (1H, d, J=9.5 Hz), 7.17(1H, d, J=9.0 Hz), 7.94 (1H, s), 8.03 (1H, d, J=9.5 Hz), 11.06 (1H, s).

Example 93 Production ofN-[6-(5-amino-2-methoxyphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide

Using N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (800mg, 2.44 mmol), 5-amino-2-methoxyphenol (408 mg, 2.93 mmol), potassiumcarbonate (843 mg, 6.10 mmol) and N,N-dimethylformamide (6.0 mL) asstarting materials and in the same manner as in Example 91, the titlecompound (299 mg, 36%) was obtained as a brown powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.71-0.85 (4H, m), 1.91 (1H, m), 3.56 (3H,s), 4.87 (2H, s), 6.41-6.49 (2H, m), 6.85-6.91 (1H, m), 6.95 (1H, d,J=9.5 Hz), 7.90 (1H, s), 7.96 (1H, d, J=9.5 Hz), 11.05 (1H, s).

Example 94 Production ofN-[6-(3-amino-2-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide

Using N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (800mg, 2.44 mmol), 3-amino-2-methylphenol (380 mg, 2.93 mmol), potassiumcarbonate (843 mg, 6.10 mmol) and N,N-dimethylformamide (6.0 mL) asstarting materials and in the same manner as in Example 91, the titlecompound (454 mg, 58%) was obtained as a blackish brown powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.71-0.87 (4H, m), 1.83-1.98 (1H, m), 1.89(3H, s), 5.13 (2H, s), 6.32 (1H, d, J=8.0 Hz), 6.55 (1H, d, J=6.8 Hz),6.93 (1H, dd, J=8.0, 6.8 Hz), 6.94 (1H, d, J=9.5 Hz), 7.91 (1H, s), 7.98(1H, d, J=9.5 Hz), 11.05 (1H, s).

Example 95 Production ofN-[6-(1H-indol-6-yloxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide

A mixture ofN-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (473 mg,1.44 mmol), 1H-indole-6-ol (250 mg, 1.87 mmol), potassium carbonate (597mg, 4.32 mmol) and N,N-dimethylformamide (4.0 mL) was stirred at 110° C.for 2 days. The solvent was evaporated under reduced pressure, ethylacetate, tetrahydrofuran and water were added to the residue, and theaqueous layer was extracted three times with ethylacetate/tetrahydrofuran. Combined organic layer was washed withsaturated brine, dried over anhydrous sodium sulfate, and filtrated. Thesolvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography (ethylacetate/hexane=20/80→85/15), and precipitated from ethyl acetate/hexaneto give the title compound (48 mg, 10%) as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.70-0.89 (4H, m), 1.83-1.97 (1H, m), 6.47(1H, s), 6.89 (1H, dd, J=8.3, 2.3 Hz), 7.00 (1H, d, J=9.5 Hz), 7.26 (1H,d, J=2.3 Hz), 7.33-7.42 (1H, m), 7.58 (1H, d, J=8.3 Hz), 7.91 (1H, s),7.99 (1H, d, J=9.5 Hz), 11.06 (1H, s), 11.17 (1H, s).

Example 96 Production ofN-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-4-methylphenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide

To a solution ofN-[6-(5-amino-2-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(72.6 mg, 0.224 mmol) in tetrahydrofuran (4.0 mL) were added a solutionof 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (46.3 mg, 0.29 mmol) intetrahydrofuran (0.5 mL) and triethylamine (68 mg, 0.672 mmol) underice-cooling, and the mixture was stirred at room temperature for 1 hr.The reaction mixture was diluted with saturated aqueous sodiumhydrogencarbonate solution, and extracted three times with ethylacetate. The organic layer was washed with saturated brine, dried overanhydrous sodium sulfate, and filtrated. The solvent was evaporatedunder reduced pressure, and the residue was filtrated, washed with ethylacetate/hexane to give the title compound (64 mg, 64%) as a brownpowder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.70-0.88 (4H, m), 1.85-1.97 (1H, m), 2.14(3H, s), 2.18 (3H, s), 3.97 (3H, s), 6.81 (1H, s), 7.08 (1H, d, J=9.5Hz), 7.32 (1H, d, J=8.3 Hz), 7.55 (1H, dd, J=8.3, 1.9 Hz), 7.60 (1H, d,J=1.9 Hz), 7.92 (1H, s), 8.05 (1H, d, J=9.5 Hz), 10.18 (1H, s), 11.08(1H, s).

Example 97 Production ofN-[2-chloro-5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide

UsingN-[6-(3-amino-4-chlorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(128 mg, 0.373 mmol), 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (77.2mg, 0.485 mmol), triethylamine (113 mg, 1.12 mmol) and tetrahydrofuran(5.0 mL) as starting materials and in the same manner as in Example 96,the title compound (77 mg, 44%) was obtained as a white powder. meltingpoint 255° C.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.72-0.86 (4H, m), 1.85-1.98 (1H, m), 2.20(3H, s), 3.98 (3H, s), 6.84 (1H, s), 7.10 (1H, d, J=9.6 Hz), 7.26 (1H,dd, J=8.9, 2.8 Hz), 7.54 (1H, d, J=2.8 Hz), 7.64 (1H, d, J=8.9 Hz), 7.96(1H, s), 8.06 (1H, d, J=9.6 Hz), 9.99 (1H, s), 11.09 (1H, s).

Example 98 Production ofN-[4-chloro-3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide

UsingN-[6-(5-amino-2-chlorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(131 mg, 0.382 mmol), 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (91mg, 0.573 mmol), triethylamine (116 mg, 1.15 mmol) and tetrahydrofuran(5.0 mL) as starting materials and in the same manner as in Example 96,the title compound (163 mg, 92%) was obtained as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.67-0.82 (4H, m), 1.81-1.94 (1H, m), 2.16(3H, s), 3.96 (3H, s), 6.80 (1H, s), 7.14 (1H, dd, J=9.6, 1.6 Hz), 7.59(1H, m), 7.66 (1H, m), 7.83 (1H, d, J=1.6 Hz), 7.91 (1H, s), 8.07 (1H,d, J=9.6 Hz), 10.34 (1H, s), 11.08 (1H, s).

Example 99 Production ofN-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-4-methoxyphenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide

UsingN-[6-(5-amino-2-methoxyphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(129 mg, 0.379 mmol), 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (78.3mg, 0.493 mmol), triethylamine (115 mg, 1.14 mmol) and tetrahydrofuran(5.0 mL) as starting materials and in the same manner as in Example 96,the title compound (124 mg, 71%) was obtained as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.72-0.85 (4H, m), 1.86-1.97 (1H, m), 2.19(3H, s), 3.71 (3H, s), 3.97 (3H, s), 6.80 (1H, s), 7.06 (1H, d, J=9.5Hz), 7.20 (1H, d, J=8.9 Hz), 7.59 (1H, dd, J=8.9, 2.5 Hz), 7.68 (1H, d,J=2.5 Hz), 7.89 (1H, s), 8.01 (1H, d, J=9.5 Hz), 10.15 (1H, s), 11.07(1H, s).

Example 100 Production ofN-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide

UsingN-[6-(3-amino-2-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(130 mg, 0.402 mmol), 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (83mg, 0.523 mmol), triethylamine (122 mg, 1.21 mmol) and tetrahydrofuran(5.0 mL) as starting materials and in the same manner as in Example 96,the title compound (146 mg, 82%) was obtained as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.72-0.87 (4H, m), 1.86-1.98 (1H, m), 2.06(3H, s), 2.20 (3H, s), 4.01 (3H, s), 6.84 (1H, s), 7.09 (1H, d, J=9.5Hz), 7.15 (1H, dd, J=6.8, 2.3 Hz), 7.25-7.36 (2H, m), 7.88 (1H, s), 8.05(1H, d, J=9.5 Hz), 9.95 (1H, s), 11.07 (1H, s).

Example 101 Production ofN-{6-[(2-methyl-1H-indol-5-yl)oxy]imidazo[1,2-b]pyridazin-2-yl}cyclopropanecarboxamide

Using N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (272mg, 0.830 mmol), 2-methyl-1H-indole-5-ol (244 mg, 1.66 mmol), potassiumcarbonate (344 mg, 2.49 mmol) and N,N-dimethylformamide (3.0 mL) asstarting materials and in the same manner as in Example 95, the titlecompound (56 mg, 19%) was obtained as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.73-0.85 (4H, m), 1.82-1.97 (1H, m), 2.39(3H, s), 6.13 (1H, s), 6.86 (1H, dd, J=8.7, 2.3 Hz), 6.95 (1H, d, J=9.5Hz), 7.23 (1H, d, J=2.3 Hz), 7.30 (1H, d, J=8.7 Hz), 7.88 (1H, s), 7.96(1H, d, J=9.5 Hz), 11.05 (2H, s).

Example 102 Production ofN-{6-[(1,2-dimethyl-1H-benzimidazol-5-yl)oxy]imidazo[1,2-b]pyridazin-2-yl}cyclopropanecarboxamide

Using N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (254mg, 0.774 mmol), 1,2-dimethyl-1H-benzimidazole-5-ol (163 mg, 1.06 mmol),potassium carbonate (267 mg, 1.94 mmol) and N,N-dimethylformamide (3.0mL) as starting materials and in the same manner as in Example 95, thetitle compound (79 mg, 28%) was obtained as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.72-0.84 (4H, m), 1.84-1.96 (1H, m), 2.54(3H, s), 3.77 (3H, s), 7.00 (1H, d, J=9.8 Hz), 7.09 (1H, dd, J=8.7, 2.3Hz), 7.39 (1H, d, J=2.3 Hz), 7.53 (1H, d, J=8.7 Hz), 7.86 (1H, s), 7.99(1H, d, J=9.8 Hz), 11.05 (1H, s).

Example 103 Production ofN-[6-(3-{[(ethylamino)carbonyl]amino}phenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide

To a solution ofN-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(160 mg, 0.517 mmol) in pyridine (4.0 mL) was added ethyl isocyanate(409 μL, 5.17 mmol), and the mixture was stirred at room temperature for24 hr. The solvent was evaporated under reduced pressure, ethyl acetateand saturated aqueous sodium hydrogencarbonate solution were added tothe residue, and the aqueous layer was extracted three times with ethylacetate. Combined organic layer was washed with saturated brine, driedover anhydrous sodium sulfate, and filtrated. The solvent was evaporatedunder reduced pressure, and the residue was filtrated, and washed withethyl acetate/hexane to give the title compound (136 mg, 69%) as a whitepowder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.72-0.86 (4H, m), 1.00 (3H, t, J=7.1 Hz),1.83-1.95 (1H, m), 2.97-3.12 (2H, m), 6.13 (1H, t, J=5.5 Hz), 6.72 (1H,dd, J=8.0, 2.5 Hz), 6.99 (1H, d, J=9.6 Hz), 7.09 (1H, dd, J=8.2, 1.1Hz), 7.25 (1H, t, J=8.2 Hz), 7.42 (1H, t, J=1.9 Hz), 7.94 (1H, s), 8.00(1H, d, J=9.6 Hz), 8.61 (1H, s), 11.08 (1H, s).

Example 104 Production ofN-[6-(1H-indol-4-yloxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide

Using N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (353mg, 1.08 mmol), 1H-indole-4-ol (241 mg, 1.82 mmol), potassium carbonate(446 mg, 3.23 mmol) and N,N-dimethylformamide (4.0 mL) as startingmaterials and in the same manner as in Example 95, the title compound(66 mg, 18%) was obtained as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.70-0.86 (4H, m), 1.83-1.96 (1H, m),6.16-6.23 (1H, m), 6.85 (1H, dd, J=7.8, 0.8 Hz), 7.01 (1H, d, J=9.6 Hz),7.12 (1H, t, J=7.8 Hz), 7.26-7.37 (2H, m), 7.89 (1H, s), 8.00 (1H, d,J=9.6 Hz), 11.06 (1H, s), 11.37 (1H, s).

Example 105 Production ofN-{6-[(2-methyl-1,3-benzothiazol-5-yl)oxy]imidazo[1,2-b]pyridazin-2-yl}cyclopropanecarboxamide

Using N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (355mg, 1.08 mmol), 2-methyl-1,3-benzothiazole-5-ol (286 mg, 1.73 mmol),potassium carbonate (448 mg, 3.24 mmol) and N,N-dimethylformamide (4.0mL) as starting materials and in the same manner as in Example 95, thetitle compound (275 mg, 70%) was obtained as a pale-yellow powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.72-0.86 (4H, m), 1.83-1.97 (1H, m), 2.82(3H, s), 7.09 (1H, d, J=9.6 Hz), 7.35 (1H, dd, J=8.7, 2.3 Hz), 7.82 (1H,d, J=2.3 Hz), 7.92 (1H, s), 8.04 (1H, d, J=9.6 Hz), 8.10 (1H, d, J=8.7Hz), 11.07 (1H, s).

Example 106 Production of3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-N-(1,3-dimethyl-1H-pyrazol-5-yl)benzamide

To a solution of3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)benzoicacid (121 mg, 0.358 mmol) in N,N-dimethylformamide (5.0 mL) were added1,3-dimethyl-1H-pyrazol-5-amine (47.8 mg, 0.43 mmol),1-hydroxybenzotriazole (58 mg, 0.43 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (82.4 mg,0.43 mmol) and triethylamine (45 mg, 0.43 mmol), and the mixture wasstirred at room temperature for 24 hr. The solvent was evaporated underreduced pressure, ethyl acetate, tetrahydrofuran and water were added tothe residue, and the aqueous layer was extracted three times with ethylacetate/tetrahydrofuran. Combined organic layer was washed withsaturated brine, dried over anhydrous sodium sulfate, and filtrated. Thesolvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography (ethylacetate/hexane=20/80→90/10, then methanol/ethyl acetate=0/100→15/85),and precipitated from ethyl acetate/hexane to give the title compound(116 mg, 75%) as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.73-0.85 (4H, m), 1.86-1.96 (1H, m), 2.12(3H, s), 3.56 (3H, s), 6.02 (1H, s), 7.11 (1H, d, J=9.6 Hz), 7.50-7.57(1H, m), 7.63 (1H, t, J=7.9 Hz), 7.79-7.92 (2H, m), 7.95 (1H, s), 8.07(1H, d, J=9.6 Hz), 10.31 (1H, s), 11.09 (1H, s).

Example 107 Production ofN-[2-chloro-5-({2[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]cyclopropanecarboxamide

UsingN-[6-(3-amino-4-chlorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(150 mg, 0.435 mmol), cyclopropanecarbonyl chloride (71.8 mg, 0.652mmol), triethylamine (132 mg, 1.30 mmol) and tetrahydrofuran (17 mL) asstarting materials and in the same manner as in Example 96, the titlecompound (156 mg, 87%) was obtained as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.70-0.89 (8H, m), 1.84-1.98 (1H, m),2.00-2.11 (1H, m), 7.06 (1H, d, J=9.6 Hz), 7.10 (1H, dd, J=8.7, 2.8 Hz),7.56 (1H, d, J=8.7 Hz), 7.73 (1H, d, J=2.8 Hz), 7.95 (1H, s), 8.04 (1H,d, J=9.6 Hz), 9.83 (1H, s), 11.09 (1H, s).

Example 108 Production ofN-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide

A mixture ofN-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (743 mg,2.26 mmol), 3-amino-4-methylphenol (446 mg, 3.62 mmol), potassiumcarbonate (782 mg, 5.66 mmol) and N,N-dimethylformamide (5.0 mL) wasstirred using a microwave synthesizer at 180° C. for 30 min. The solventwas evaporated under reduced pressure, ethyl acetate, tetrahydrofuranand water were added to the residue, and the aqueous layer was extractedthree times with ethyl acetate/tetrahydrofuran. Combined organic layerwas washed with saturated brine, dried over anhydrous sodium sulfate,and filtrated. The solvent was evaporated under reduced pressure, andthe residue was purified by silica gel column chromatography (ethylacetate/hexane=17/83→75/25) to give the title compound (424 mg, 58%) asa brown powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.72-0.86 (4H, m), 1.84-1.97 (1H, m), 2.04(3H, s), 5.06 (2H, s), 6.28 (1H, dd, J=8.1, 2.4 Hz), 6.42 (1H, d, J=2.4Hz), 6.93 (1H, d, J=9.3 Hz), 6.95 (1H, d, J=8.1 Hz), 7.96 (1H, s), 7.98(1H, d, J=9.3 Hz), 11.07 (1H, s).

Example 109 Production ofN-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-3-methylisoxazole-5-carboxamide

To a solution of 3-methylisoxazole-5-carboxylic acid (87 mg, 0.679 mmol)in tetrahydrofuran (2.0 mL) were added N,N-dimethylformamide (1 drop)and oxalyl chloride (75.8 μL, 0.88 mmol), and the mixture was stirred atroom temperature for 30 min. The solvent was evaporated under reducedpressure, and the residue was dissolved in tetrahydrofuran (1 mL), andadded to a solution ofN-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(140 mg, 0.453 mmol) in tetrahydrofuran (12 mL). Then, triethylamine(138 mg, 1.36 mmol) was added to the mixture, and the mixture wasstirred at room temperature for 30 min. The reaction mixture was dilutedwith saturated aqueous sodium hydrogencarbonate solution, and extractedthree times with ethyl acetate, and the organic layer was washed withsaturated brine, dried over anhydrous sodium sulfate, and filtrated. Thesolvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography (ethylacetate/hexane=20/80→80/20) and precipitated from ethyl acetate/hexaneto give the title compound (42 mg, 22%) as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.73-0.87 (4H, m), 1.86-1.98 (1H, m), 2.32(3H, s), 7.01-7.14 (3H, m), 7.45 (1H, t, J=8.2 Hz), 7.62-7.74 (2H, m),7.98 (1H, s), 8.06 (1H, d, J=9.8 Hz), 10.82 (1H, s), 11.10 (1H, s).

Example 110 Production ofN-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-5-methylisoxazole-3-carboxamide

Using 5-methylisoxazole-3-carboxylic acid (87 mg, 0.679 mmol),N,N-dimethylformamide (1 drop), oxalyl chloride (75.8 μL, 0.88 mmol),N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(140 mg, 0.453 mmol), triethylamine (138 mg, 1.36 mmol) andtetrahydrofuran (15 mL) as starting materials and in the same manner asin Example 109, the title compound (109 mg, 58%) was obtained as a whitepowder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.73-0.86 (4H, m), 1.85-1.96 (1H, m), 2.50(3H, s), 6.6.6 (1H, d, J=0.9 Hz), 6.97-7.10 (2H, m), 7.43 (1H, t, J=8.2Hz), 7.63-7.77 (2H, m), 7.98 (1H, s), 8.05 (1H, d, J=9.4 Hz), 10.78 (1H,s), 11.09 (1H, s).

Example 111 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide

To a solution ofN-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(213 mg, 0.659 mmol) in tetrahydrofuran (10 mL) were added a solution of1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (136 mg, 0.856 mmol) intetrahydrofuran (0.5 mL) and triethylamine (200 mg, 1.98 mmol) underice-cooling, and the mixture was stirred at room temperature for 1 hr.The reaction mixture was diluted with saturated aqueous sodiumhydrogencarbonate solution, and extracted three times with ethylacetate, and the organic layer was washed with saturated brine, driedover anhydrous sodium sulfate, and filtrated. The solvent was evaporatedunder reduced pressure, and the residue was filtrated and washed withethyl acetate/hexane to give the title compound (222 mg, 77%) as a whitepowder. melting point 223° C.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.72-0.89 (4H, m), 1.86-1.97 (1H, m), 2.19(3H, s), 2.25 (3H, s), 3.98 (3H, s), 6.81 (1H, s), 7.04 (1H, d, J=9.6Hz), 7.10 (1H, dd, J=8.7, 2.4 Hz), 7.28 (1H, d, J=2.4 Hz), 7.35 (1H, d,J=8.7 Hz), 7.93 (1H, s), 8.03 (1H, d, J=9.6 Hz), 9.81 (1H, s), 11.08(1H, s).

Example 112 Production ofN-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide

Using 1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (100mg, 0.515 mmol), N,N-dimethylformamide (1 drop), oxalyl chloride (60 μL,0.7 mmol),N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(122.5 mg, 0.396 mmol), triethylamine (120 mg, 1.19 mmol) andtetrahydrofuran (15 mL) as starting materials and in the same manner asin Example 109, the title compound (149 mg, 78%) was obtained as a whitepowder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.73-0.85 (4H, m), 1.84-1.97 (1H, m), 4.15(3H, s), 7.05 (1H, m), 7.08 (1H, d, J=9.6 Hz), 7.46 (1H, t, J=8.2 Hz),7.50 (1H, s), 7.59-7.64 (1H, m), 7.66 (1H, t, J=2.1 Hz), 7.98 (1H, s),8.06 (1H, d, J=9.6 Hz), 10.53 (1H, s), 11.10 (1H, s).

Example 113 Production ofN-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-5-methyl-2-(trifluoromethyl)-3-furancarboxamide

Using 5-methyl-2-(trifluoromethyl)-3-furancarboxylic acid (133.6 mg,0.668 mmol), N,N-dimethylformamide (1 drop), oxalyl chloride (75 μL,0.868 mmol),N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(159 mg, 0.514 mmol), triethylamine (156 mg, 1.54 mmol) andtetrahydrofuran (15 mL) as starting materials and in the same manner asin Example 109, the title compound (145 mg, 58%) was obtained as a whitepowder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.73-0.86 (4H, m), 1.85-1.97 (1H, m), 2.40(3H, s), 6.80 (1H, s), 7.02 (1H, m), 7.06 (1H, d, J=9.6 Hz), 7.43 (1H,t, J=8.2 Hz), 7.56 (1H, d, J=8.3 Hz), 7.63 (1H, t, J=2.0 Hz), 7.97 (1H,s), 8.05 (1H, d, J=9.6 Hz), 10.50 (1H, s), 11.09 (1H, s).

Example 114 Production ofN-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-2,4-dimethyl-1,3-thiazole-5-carboxamide

Using 2,4-dimethyl-1,3-thiazole-5-carboxylic acid (78.8 mg, 0.50 mmol),N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(129 mg, 0.417 mmol), 1-hydroxybenzotriazole (68 mg, 0.50 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (96 mg, 0.50mmol), triethylamine (50 mg, 0.50 mmol) and N,N-dimethylformamide (5.0mL) as starting materials and in the same manner as in Example 106, thetitle compound (133 mg, 71%) was obtained as a white powder. meltingpoint 249° C.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.74-0.88 (4H, m), 1.85-1.98 (1H, m), 2.53(3H, s), 2.65 (3H, s), 7.00 (1H, dd, J=7.6, 1.9 Hz), 7.06 (1H, d, J=9.5Hz), 7.41 (1H, t, J=8.1 Hz), 7.54 (1H, d, J=8.3 Hz), 7.62 (1H, t, J=2.1Hz), 7.97 (1H, s), 8.05 (1H, d, J=9.5 Hz), 10.22 (1H, s), 11.09 (1H, s).

Example 115 Production ofN-{6-[(2-methyl-1,3-benzothiazol-6-yl)oxy]imidazo[1,2-b]pyridazin-2-yl}cyclopropanecarboxamide

Using N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (309mg, 0.942 mmol), 2-methyl-1,3-benzothiazole-6-ol (250 mg, 1.51 mmol),potassium carbonate (390 mg, 2.83 mmol) and N,N-dimethylformamide (4.0mL) as starting materials and in the same manner as in Example 95, thetitle compound (151 mg, 44%) was obtained as a pale-yellow powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.71-0.83 (4H, m), 1.83-1.94 (1H, m), 2.79(3H, s), 7.07 (1H, d, J=9.6 Hz), 7.37 (1H, dd, J=8.8, 2.5 Hz), 7.90-7.99(3H, m), 8.02 (1H, d, J=9.6 Hz), 11.06 (1H, s).

Example 116 Production ofN-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-3-methyl-1-(2,2,2-trifluoroethyl)-1H-pyrazole-5-carboxamide

Using 3-methyl-1-(2,2,2-trifluoroethyl)-1H-pyrazole-5-carboxylic acid(175 mg, 0.84 mmol), N,N-dimethylformamide (1 drop), oxalyl chloride (91μL, 1.01 mmol),N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(200 mg, 0.646 mmol), triethylamine (196 mg, 1.94 mmol) andtetrahydrofuran (15 mL) as starting materials and in the same manner asin Example 109, the title compound (281 mg, 87%) was obtained as a whitepowder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.73-0.86 (4H, m), 1.87-1.98 (1H, m), 2.25(3H, s), 5.40 (2H, q, J=8.9 Hz), 7.00 (1H, s), 7.04 (1H, m), 7.07 (1H,d, J=9.4 Hz), 7.45 (1H, t, J=8.2 Hz), 7.58-7.69 (2H, m), 7.97 (1H, s),8.06 (1H, d, J=9.4 Hz), 10.45 (1H, s), 11.10 (1H, s).

Example 117 Production ofN-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-2,5-dimethyl-1,3-oxazole-4-carboxamide

To a solution ofN-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(202 mg, 0.652 mmol) in N,N-dimethylacetamide (4.0 mL) was added asolution of 2,5-dimethyl-1,3-oxazole-4-carbonyl chloride (135 mg, 0.847mmol) in N,N-dimethylacetamide (1.0 mL), and the mixture was stirred at0° C. for 1 hr. Ethyl acetate/tetrahydrofuran and saturated aqueoussodium hydrogencarbonate solution were added to the mixture, and theaqueous layer was extracted three times with ethylacetate/tetrahydrofuran. Combined organic layer was washed withsaturated brine, dried over anhydrous sodium sulfate, and filtrated. Thesolvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography (ethylacetate/hexane=20/80→490/10), and precipitated from ethyl acetate/hexaneto give the title compound (213 mg, 76%) as a white powder. meltingpoint 224° C.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.73-0.87 (4H, m), 1.87-1.97 (1H, m), 2.44(3H, s), 2.56 (3H, s), 6.96 (1H, dd, J=8.3, 2.1 Hz), 7.05 (1H, d, J=9.5Hz), 7.38 (1H, t, J=8.1 Hz), 7.72 (1H, d, J=8.3 Hz), 7.80 (1H, t, J=2.1Hz), 7.98 (1H, s), 8.04 (1H, d, J=9.5 Hz), 10.12 (1H, s), 11.09 (1H, s).

Example 118 Production ofN-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-1-methyl-1H-pyrazole-5-carboxamide

To a solution of 1-methyl-1H-pyrazole-5-carboxylic acid (106 mg, 0.840mmol) in tetrahydrofuran (2.0 mL) were added N,N-dimethylformamide (1drop) and oxalyl chloride (91 μL, 1.01 mmol), and the mixture wasstirred at room temperature for 30 min. The solvent was evaporated underreduced pressure, and the residue was dissolved in N,N-dimethylacetamide(1 mL) and added to a solution ofN-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(200 mg, 0.646 mmol) in N,N-dimethylacetamide (5.0 mL). The mixture wasstirred at room temperature for 30 min. The reaction mixture was dilutedwith saturated aqueous sodium hydrogencarbonate solution, and extractedthree times with ethyl acetate, and the organic layer was washed withsaturated brine, dried over anhydrous sodium sulfate, and filtrated. Thesolvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography (ethylacetate/hexane=30/70→95/5) and precipitated from ethyl acetate/hexane togive the title compound (241 mg, 89%) as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.75-0.87 (4H, m), 1.86-1.98 (1H, m), 4.07(3H, s), 7.00-7.05 (1H, m), 7.04-7.10 (2H, m), 7.44 (1H, t, J=8.2 Hz),7.53 (1H, d, J=2.1 Hz), 7.59-7.69 (2H, m), 7.98 (1H, s), 8.06 (1H, d,J=9.6 Hz), 10.33 (1H, s), 11.10 (1H, s).

Example 119 Production ofN-(3-{[2-(acetylamino)imidazo[1,2-b]pyridazin-6-yl]oxy}phenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide

To a solution (4.0 mL) of 1,3-dimethyl-1H-pyrazole-5-carboxylic acid(109 mg, 0.85 mmol) in tetrahydrofuran were added N,N-dimethylformamide(30 μL, 0.39 mmol) and oxalyl chloride (135 μL, 1.55 mmol), and themixture was stirred at room temperature for 1 hr. The solvent wasevaporated under reduced pressure, and a solution of the residue inN,N-dimethylacetamide (2.0 mL) was added dropwise to a solution ofN-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]acetamide (200 mg,0.71 mmol) in N,N-dimethylacetamide (2.0 mL). After the reaction mixturewas stirred at room temperature for 1 hr, water was added to thereaction mixture, and the mixture was extracted with ethylacetate/tetrahydrofuran, washed with saturated brine, dried overanhydrous magnesium sulfate, and filtrated. The solvent was evaporatedunder reduced pressure, and the residue was washed with ethyl acetate togive the title compound (182 mg, 67%) as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 2.07 (3H, s), 2.19 (3H, s), 3.97 (3H, s),6.82 (1H, s), 6.98-7.03 (1H, m), 7.06 (1H, d, J=9.6 Hz), 7.42 (1H, t,J=8.1 Hz), 7.59-7.63 (1H, m), 7.66-7.68 (1H, m), 7.98 (1H, s), 8.04 (1H,d, J=9.6 Hz), 10.24 (1H, s), 10.80 (1H, s).

Example 120 Production ofN-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide

To a solution ofN-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(200 mg, 0.65 mmol) in N,N-dimethylacetamide (2.0 mL) was added1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (185 mg, 1.16 mmol). Afterstirring at room temperature for 1 hr, water was added to the reactionmixture, and the mixture was extracted with ethylacetate/tetrahydrofuran, washed with saturated brine, dried overanhydrous magnesium sulfate, and filtrated. The solvent was evaporatedunder reduced pressure, and the residue was purified by silica gelcolumn chromatography (hexane/ethyl acetate=1/2→4-ethyl acetate) andprecipitated from hexane/ethyl acetate to give the title compound (70mg, 25%) as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.79-0.83 (4H, m), 1.87-1.97 (1H, m), 2.19(3H, s), 3.98 (3H, s), 6.82 (1H, s), 6.99-7.03 (1H, m), 7.07 (1H, d,J=9.6 Hz), 7.43 (1H, t, J=8.1 Hz), 7.60-7.64 (1H, m), 7.65-7.68 (1H, m),7.97 (1H, s), 8.06 (1H, d, J=9.6 Hz), 10.24 (1H, s), 11.10 (1H, s).

Example 121 Production of1,3-dimethyl-N-[3-({2-[(tetrahydro-2H-pyran-4-ylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-1H-pyrazole-5-carboxamide

UsingN-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]tetrahydro-2H-pyran-4-carboxamide(200 mg, 0.57 mmol), triethylamine (237 mL, 1.70 mmol),1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (180 mg, 1.13 mmol) andtetrahydrofuran (6.0 mL) as starting materials and in the same manner asin Example 96, the title compound (73 mg, 27%) was obtained as a whitepowder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.58-1.72 (4H, m), 2.20 (3H, s), 2.63-2.78(1H, m), 3.27-3.37 (2H, m), 3.86-3.92 (2H, s), 3.98 (3H, s), 6.83 (1H,s), 6.98-7.03 (1H, m), 7.07 (1H, d, J=9.6 Hz), 7.43 (1H, t, J=8.1 Hz),7.59-7.63 (1H, m), 7.67-7.70 (1H, m), 8.03 (1H, s), 8.06 (1H, d, J=9.6Hz), 10.26 (1H, s), 10.82 (1H, s).

Example 122 Production ofN-[6-(4-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide

To a solution of 4-aminophenol (0.33 g, 3.05 mmol) inN,N-dimethylformamide (10 mL) was added potassium tert-butoxide (0.36 g,3.17 mmol), and the mixture was stirred at room temperature for 2 hr. N(6-Iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (0.80 g,2.44 mmol) and potassium carbonate (0.17 g, 1.22 mmol) were added to thereaction mixture, and the mixture was stirred using a microwavesynthesizer with heating at 150° C. for 30 min. After cooling thereaction mixture, saturated brine was added to the mixture, and themixture was extracted with ethyl acetate/tetrahydrofuran, washed withsaturated brine, dried over anhydrous magnesium sulfate, and filtrated.The solvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography (hexane/ethylacetate=1/2→ethyl acetate) to give the title compound (376 mg, 50%) as adark brown powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.76-0.81 (4H, m), 1.88-1.95 (1H, m), 5.09(2H, s), 6.57-6.61 (2H, s), 6.88-6.94 (3H, m), 7.89-7.97 (2H, m), 11.05(1H, s).

Example 123 Production ofN-[4-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide

UsingN-[6-(4-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(220 mg, 0.71 mmol), triethylamine (0.30 mL, 2.13 mmol),1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (230 mg, 1.42 mmol) andtetrahydrofuran (6.6 mL) as starting materials and in the same manner asin Example 96, the title compound (84 mg, 27%) was obtained as a whitepowder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.78-0.82 (4H, m), 1.87-1.96 (1H, m), 2.21(3H, s), 4.00 (3H, s), 6.82 (1H, s), 7.03 (1H, d, J=9.6 Hz), 7.25 (2H,d, J=9.0 Hz), 7.78 (2H, d, J=9.0 Hz), 7.92 (1H, s), 8.02 (1H, d, J=9.6Hz), 10.22 (1H, s), 11.07 (1H, s).

Example 124 Production of6-(3-aminophenoxy)-N-methylimidazo[1,2-b]pyridazine-2-carboxamide

Using 6-iodo-N-methylimidazo[1,2-b]pyridazine-2-carboxamide (0.30 g,0.99 mmol), N,N-dimethylformamide (3.0 mL), potassium carbonate (275 mg,1.99 mmol) and 3-aminophenol (163 mg, 1.49 mmol) as starting materialsand in the same manner as in Example 91, the title compound (0.10 g,36%) was obtained as a dark brown powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 2.77 (3H, d, J=5.1 Hz), 5.34 (2H, s),6.32-6.40 (2H, m), 6.43-6.47 (1H, m), 7.06 (1H, t, J=8.1 Hz), 7.13 (1H,d, J=9.6 Hz), 8.15 (1H, d, J=9.6 Hz), 8.34 (1H, s), 8.37 (1H, q, J=5.1Hz).

Example 125 Production of6-(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenoxy)-N-methylimidazo[1,2-b]pyridazine-2-carboxamide

To a solution of6-(3-aminophenoxy)-N-methylimidazo[1,2-b]pyridazine-2-carboxamide (250mg, 0.88 mmol) in N,N-dimethylacetamide (2.5 mL) was added1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (253 mg, 1.59 mmol). Afterstirring at room temperature for 1 hr, water was added to the reactionmixture, and the precipitate was collected by filtration. The obtainedresidue was washed with water, acetonitrile and diethyl ether to givethe title compound (262 mg, 73%) as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 2.20 (3H, s), 2.77 (3H, d, J=5.1 Hz), 3.99(3H, s), 6.82 (1H, s), 7.04-7.09 (1H, m), 7.24 (1H, d, J=9.9 Hz), 7.44(1H, t, J=8.1 Hz), 7.57-7.64 (1H, m), 7.71-7.74 (1H, m), 8.20 (1H, d,J=9.6 Hz), 8.34 (1H, s), 8.35-8.41 (1H, m), 10.28 (1H, s).

Example 126 Production ofN-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]-2-methoxyacetamide

Using N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)-2-methoxyacetamide (0.60 g,1.81 mmol), N,N-dimethylformamide (6.0 mL), potassium carbonate (499 mg,3.61 mmol) and 3-aminophenol (296 mg, 2.71 mmol) as starting materialsand in the same manner as in Example 91, the title compound (0.29 g,51%) was obtained as a dark brown powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 3.35 (3H, s), 4.06 (2H, s), 5.32 (2H, s),6.28-6.37 (2H, s), 6.41-6.45 (1H, m), 6.98 (1H, d, J=9.6 Hz), 7.05 (1H,t, J=8.1 Hz), 8.01 (1H, d, J=9.6 Hz), 8.04 (1H, s), 10.57 (1H, s).

Example 127 Production ofN-[3-({2-[(methoxyacetyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide

UsingN-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]-2-methoxyacetamide(200 mg, 0.64 mmol), 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (162mg, 1.02 mmol) and N,N-dimethylacetamide (4.0 mL) as starting materialsand in the same manner as in Example 120, the title compound (176 mg,64%) was obtained as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 2.19 (3H, s), 3.33 (3H, s), 3.98 (3H, s),4.06 (2H, s), 6.82 (1H, s), 6.97-7.04 (1H, m), 7.09 (1H, d, J=9.3 Hz),7.43 (1H, t, J=8.1 Hz), 7.58-7.64 (1H, m), 7.66-7.69 (1H, m), 8.03 (1H,s), 8.04 (1H, d, J=9.3 Hz), 10.24 (1H, s), 10.59 (1H, s).

Example 128 Production ofN-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-1,5-dimethyl-1H-pyrazole-3-carboxamide

To a solution of 1,5-dimethyl-1H-pyrazole-3-carboxylic acid (109 mg,0.78 mmol) in tetrahydrofuran (4.0 mL) were added N,N-dimethylformamide(30 μL, 0.39 mmol) and oxalyl chloride (135 μL, 1.55 mmol), and themixture was stirred at room temperature for 1 hr. The solvent wasevaporated under reduced pressure, and a solution of the residue intetrahydrofuran (2.0 mL) was added dropwise to a solution ofN-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropylcarboxamide(200 mg, 0.65 mmol) and triethylamine (360 μL, 2.59 mmol) intetrahydrofuran (4.0 mL). After stirring at room temperature for 2 hr,water was added to the reaction mixture, and the mixture was extractedwith ethyl acetate/tetrahydrofuran, washed with saturated brine, driedover anhydrous magnesium sulfate, and filtrated. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography (hexane/ethyl acetate=1/4→ethylacetate) and precipitated from hexane/ethyl acetate to give the titlecompound (118 mg, 42%) as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.78-0.83 (4H, m), 1.88-1.96 (1H, m), 2.30(3H, s), 3.82 (3H, s), 6.54 (1H, s), 6.91-6.96 (1H, m), 7.05 (1H, d,J=9.6 Hz), 7.37 (1H, t, J=8.1 Hz), 7.69-7.73 (1H, m), 7.76-7.78 (1H, m),7.97 (1H, s), 8.04 (1H, d, J=9.6 Hz), 10.10 (1H, s), 11.09 (1H, s).

Example 129 Production ofN-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]-2-methylpropanamide

Using N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)-2-methylpropanamide (0.60g, 1.82 mmol), N,N-dimethylformamide (6.0 mL), potassium carbonate (502mg, 3.63 mmol) and 3-aminophenol (278 mg, 2.54 mmol) as startingmaterials and in the same manner as in Example 91, the title compound(0.26 g, 47%) was obtained as a dark brown powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.09 (6H, d, J=6.9 Hz), 2.66-2.74 (1H, m),5.32 (2H, s), 6.27-6.36 (2H, m), 6.40-6.44 (1H, m), 6.95 (1H, d, J=9.6Hz), 7.05 (1H, t, J=8.1 Hz), 7.94-8.02 (2H, m), 10.74 (1H, s).

Example 130 Production ofN-(3-{[2-(isobutyrylamino)imidazo[1,2-b]pyridazin-6-yl]oxy}phenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide

Using 1,3-dimethyl-1H-pyrazole-5-carboxylic acid (108 mg, 0.77 mmol),tetrahydrofuran (3.2 mL), N,N-dimethylformamide (30 μL, 0.39 mmol),oxalyl chloride (134 μL, 1.54 mmol),N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]-2-methylpropanamide(200 mg, 0.64 mmol) and N,N-dimethylacetamide (4.0 mL) as startingmaterials and in the same manner as in Example 119, the title compound(201 mg, 72%) was obtained as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.08 (6H, d, J=6.9 Hz), 2.19 (3H, s),2.65-2.74 (1H, m), 3.98 (3H, s), 6.82 (1H, s), 6.98-7.02 (1H, m), 7.06(1H, d, J=9.6 Hz), 7.42 (1H, t, J=8.1 Hz), 7.59-7.63 (1H, m), 7.66-7.68(1H, m), 8.01 (1H, s), 8.04 (1H, d, J=9.6 Hz), 10.24 (1H, s), 10.75 (1H,s).

Example 131 Production ofN-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-3,5-dimethylisoxazole-4-carboxamide

UsingN-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropylcarboxamide(160 mg, 0.52 mmol), N,N-dimethylacetamide (3.2 mL) and3,5-dimethylisoxazole-4-carbonyl chloride (99 mg, 0.62 mmol) and in thesame manner as in Example 120, the title compound (163 mg, 73%) wasobtained as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.79-0.82 (4H, m), 1.88-1.95 (1H, m), 2.32(3H, s), 2.54 (3H, s), 6.98-7.02 (1H, m), 7.06 (1H, d, J=9.6 Hz), 7.42(1H, t, J=8.1 Hz), 7.48-7.51 (1H, m), 7.61-7.64 (1H, m), 7.96 (1H, s),8.05 (1H, d, J=9.6 Hz), 10.19 (1H, s), 11.09 (1H, s).

Example 132 Production ofN-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-1-methyl-1H-1,2,3-triazole-5-carboxamide

Using 1-methyl-1H-1,2,3-triazole-5-carboxylic acid (99 mg, 0.78 mmol),tetrahydrofuran (4.0 mL), N,N-dimethylformamide (30 μL, 0.39 mmol),oxalyl chloride (135 μL, 1.55 mmol),N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropylcarboxamide(200 mg, 0.65 mmol) and N,N-dimethylacetamide (4.0 mL) as startingmaterials and in the same manner as in Example 119, the title compound(182 mg, 67%) was obtained as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.79-0.82 (4H, m), 1.87-1.96 (1H, m), 4.23(3H, s), 7.02-7.09 (2H, m), 7.46 (1H, t, J=8.1 Hz), 7.56-7.65 (2H, m),7.96 (1H, s), 8.05 (1H, d, J=9.6 Hz), 8.37 (1H, s), 10.61 (1H, s), 11.09(1H, s).

Example 133 Production ofN-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-1-methyl-1H-1,2,3-triazole-4-carboxamide

Using 1-methyl-1H-1,2,3-triazole-4-carboxylic acid (99 mg, 0.78 mmol),tetrahydrofuran (4.0 mL), N,N-dimethylformamide (30 mL, 0.39 mmol),oxalyl chloride (135 μL, 1.55 mmol),N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropylcarboxamide(200 mg, 0.65 mmol) and N,N-dimethylacetamide (4.0 mL) as startingmaterials and in the same manner as in Example 119, the title compound(189 mg, 70%) was obtained as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.79-0.82 (4H, m), 1.87-1.96 (1H, m), 4.12(3H, s), 6.98 (1H, dd, J=11.3, 2.3 Hz), 7.06 (1H, d, J=9.3 Hz), 7.40(1H, t, J=8.1 Hz), 7.72-7.76 (1H, m), 7.78-7.81 (1H, m), 7.97 (1H, s),8.04 (1H, d, J=9.3 Hz), 8.66 (1H, s), 10.60 (1H, s), 11.09 (1H, s).

Example 134 Production ofN-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]propaneamide

To a solution of 3-aminophenol (331 mg, 3.0 mol) inN,N-dimethylformamide (8.0 mL) was added potassium tert-butoxide (355mg, 3.16 mmol), and the mixture was stirred at room temperature for 2hr. To the reaction mixture were addedN-(6-iodoimidazo[1,2-b]pyridazin-2-yl)propaneamide (0.80 g, 2.53 mmol)and potassium carbonate (175 mg, 1.27 mmol), and the mixture was stirredat 140° C. for 16 hr. Saturated brine was added to the reaction mixture,and the mixture was extracted with ethyl acetate/tetrahydrofuran, washedwith saturated brine, dried over anhydrous magnesium sulfate, andfiltrated. The solvent was evaporated under reduced pressure, and theresidue was purified by silica gel column chromatography (hexane/ethylacetate=1/2) and precipitated from hexane/ethyl acetate to give thetitle compound (420 mg, 56%) as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.07 (3H, t, J=7.5 Hz), 2.37 (2H, q, J=7.5Hz), 5.31 (2H, s), 6.27-6.35 (2H, m), 6.40-6.44 (1H, m), 6.95 (1H, d,J=9.3 Hz), 7.04 (1H, d, J=8.0 Hz), 7.98 (1H, d, J=9.3 Hz), 8.00 (1H, d,J=1.5 Hz), 10.73 (1H, s).

Example 135 Production of1,3-dimethyl-N-(3-{[2-(propionylamino)imidazo[1,2-b]pyridazin-6-yl]oxy}phenyl)-1H-pyrazole-5-carboxamide

Using 1,3-dimethyl-1H-pyrazole-5-carboxylic acid (113 mg, 0.81 mol),tetrahydrofuran (4.0 mL), N,N-dimethylformamide (30 μL, 0.39 mmol),oxalyl chloride (141 μL, 1.61 mmol),N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]propionyl carboxamide(200 mg, 0.67 mmol) and N,N-dimethylacetamide (4.0 mL) as startingmaterials and in the same manner as in Example 119, the title compound(190 mg, 67%) was obtained as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.07 (3H, t, J=7.5 Hz), 2.19 (3H, s), 2.37(2H, q, J=7.5 Hz), 3.98 (3H, s), 6.83 (1H, s), 6.99-7.04 (1H, m), 7.07(1H, d, J=9.6 Hz), 7.43 (1H, t, J=8.1 Hz), 7.60-7.64 (1H, m), 7.67-7.69(1H, m), 8.02 (1H, s), 8.05 (1H, d, J=9.6 Hz), 10.25 (1H, s), 10.77 (1H,s).

Example 136 Production ofN-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-1-methyl-1H-imidazole-2-carboxamide

Using 1-methyl-1H-imidazole-2-carboxylic acid (36.7 mg, 0.29 mol),tetrahydrofuran (1.5 mL), N,N-dimethylformamide (30 μL, 0.39 mmol),oxalyl chloride (51 μL, 0.58 mmol),N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropylcarboxamide(75 mg, 0.24 mmol) and N,N-dimethylacetamide (1.5 mL) as startingmaterials and in the same manner as in Example 119, the title compound(48 mg, 47%) was obtained as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.78-0.82 (4H, m), 1.91-1.97 (1H, m), 3.97(3H, s), 6.97 (1H, dd, J=8.1, 1.5 Hz), 7.05 (1H, d, J=9.6 Hz), 7.07 (1H,s), 7.39 (1H, t, J=8.1 Hz), 7.44-7.45 (1H, m), 7.72 (1H, d, J=8.4 Hz),7.78-7.80 (1H, m), 7.97 (1H, s), 8.04 (1H, d, J=9.6 Hz), 10.43 (1H, s),11.08 (1H, s).

Example 137 Production ofN-(3-{[2-(acetylamino)imidazo[1,2-b]pyridazin-6-yl]oxy}phenyl)-1-methyl-1H-imidazole-5-carboxamide

Using 1-methyl-1H-imidazole-5-carboxylic acid (80 mg, 0.64 mol),tetrahydrofuran (3.0 mL), N,N-dimethylformamide (30 μL, 0.39 mmol),oxalyl chloride (111 μL, 1.27=mol),N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]acetamide (150 mg,0.53 mmol) and N,N-dimethylacetamide (3.0 mL) as starting materials andin the same manner as in Example 119, the title compound (98 mg, 47%)was obtained as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 2.07 (3H, s), 3.84 (3H, s), 6.96-7.00 (1H,m), 7.06 (1H, d, J=9.3 Hz), 7.42 (1H, t, J=8.1 Hz), 7.57-7.61 (1H, m),7.64-7.67 (1H, m), 7.79 (1H, s), 7.84 (1H, s), 7.99 (1H, s), 8.05 (1H,d, J=9.3 Hz), 10.16 (1H, s), 10.81 (1H, s).

Example 138 Production ofN-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide

A mixture ofN-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (2.62 g,8.0 mmol), 3-amino-4-fluorophenol (2.03 g, 16.0 mmol), potassiumcarbonate (1.66 g, 12.0 mmol) and N,N-dimethylformamide (20 mL) wasstirred at 150° C. for 15 hr. Tetrahydrofuran/ethyl acetate andsaturated brine were added to the reaction mixture, and insolublematerial was filtered off. The filtrate was extracted with ethylacetate, dried over anhydrous magnesium sulfate, and filtrated. Thesolvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography (hexane/ethylacetate=20/80→0/100) and recrystallized from ethyl acetate to give thetitle compound (1.91 g, 73%) as pale-yellow crystals.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.75-0.90 (4H, m), 1.85-2.00 (1H, m), 5.36(2H, s), 6.30-6.40 (1H, m), 6.50-6.60 (1H, m), 6.96 (1H, d, J=9.8 Hz),7.00-7.10 (1H, m), 7.95 (1H, s), 7.99 (1H, d, J=9.8 Hz), 11.06 (1H, s).

Example 139 Production of 4-(imidazo[1,2-b]pyridazin-6-yloxy)aniline

A mixture of 6-chloroimidazo[1,2-b]pyridazine (768 mg, 5.0 mmol),4-aminophenol (818 mg, 7.5 mmol), potassium carbonate (2073 mg, 15.0mmol) and N-methylpyrrolidone (5.0 mL) was stirred at 120° C. for 18 hr.The reaction mixture was diluted with 1N aqueous sodium hydroxidesolution, and extracted with ethyl acetate. The organic layer was washedwith 1N aqueous sodium hydroxide solution and saturated brine, andconcentrated under reduced pressure. The residue was purified by NHsilica gel column chromatography (hexane/ethyl acetate=70/30→0/100) andprecipitated from diisopropyl ether to give the title compound (759 mg,67%) as a gray powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 5.07 (2H, s), 6.60 (2H, d, J=8.9 Hz), 6.92(2H, d, J=8.9 Hz), 7.00 (1H, d, J=9.8 Hz), 7.61 (1H, s), 8.01 (1H, s),8.09 (1H, d, J=9.8 Hz).

Example 140 3-(imidazo[1,2-b]pyridazin-6-yloxy)aniline

A mixture of 6-chloroimidazo[1,2-b]pyridazine (1536 mg, 10.0 mmol),3-aminophenol (1419 mg, 13.0 mmol), potassium carbonate (4146 mg, 30.0mmol) and N-methylpyrrolidone (10 mL) was stirred at 120° C. for 48 hr.The reaction mixture was diluted with 1N aqueous sodium hydroxidesolution, and extracted with ethyl acetate. The organic layer was washedwith 1N aqueous sodium hydroxide solution and saturated brine, andconcentrated under reduced pressure. The residue was purified by NHsilica gel column chromatography (hexane/ethyl acetate=70/30→0/100), andprecipitated from diisopropyl ether to give the title compound (932 mg,41%) as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 5.29 (2H, s), 6.31-6.35 (1H, m), 6.37 (1H,t, J=2.2 Hz), 6.42-6.47 (1H, m), 7.02 (1H, d, J=9.8 Hz), 7.06 (1H, t,J=7.9 Hz), 7.65 (1H, d, J=1.2 Hz), 8.08 (1H, s), 8.13 (1H, d, J=9.8 Hz).

Example 141 Production ofN-[4-(imidazo[1,2-b]pyridazin-6-yloxy)phenyl]-N′-phenylurea

To a solution of 4-(imidazo[1,2-b]pyridazin-6-yloxy)aniline (181 mg,0.80 mmol) and triethylamine (0.011 mL, 0.08 mmol) in tetrahydrofuran(10 mL) was added phenyl isocyanate (0.104 mL, 0.96 mmol), and themixture was stirred at room temperature for 18 hr. The reaction mixturewas concentrated under reduced pressure, and the residue was purified byNH silica gel column chromatography (ethyl acetate/methanol=100/0→90/10)and precipitated from ethyl acetate to give the title compound (223 mg,81%) as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 6.97 (1H, t, J=7.6 Hz), 7.09 (1H, d, J=9.8Hz), 7.22 (2H, d, J=8.7 Hz), 7.28 (2H, t, J=7.6 Hz), 7.46 (2H, d, J=7.6Hz), 7.52 (2H, d, J=8.7 Hz), 7.64 (1H, s), 8.05 (1H, s), 8.15 (1H, d,J=9.8 Hz), 8.70 (1H, s), 8.76 (1H, s).

Example 142 Production ofN-[3-(imidazo[1,2-b]pyridazin-6-yloxy)phenyl]-N′-phenylurea

To a solution of 3-(imidazo[1,2-b]pyridazin-6-yloxy)aniline (181 mg,0.80 mmol) and triethylamine (0.011 mL, 0.08 mmol) in tetrahydrofuran(10 mL) was added phenyl isocyanate (0.104 mL, 0.96 mmol), and themixture was stirred at room temperature for 18 hr. The reaction mixturewas concentrated under reduced pressure, and the residue was purified byNH silica gel column chromatography (ethyl acetate/methanol=100/0→90/10)and precipitated from ethyl acetate to give the title compound (196 mg,71%) as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 6.85-6.90 (1H, m), 6.97 (1H, t, J=7.5 Hz),7.11 (1H, d, J=9.6 Hz), 7.22-7.31 (3H, m), 7.36 (1H, t, J=7.9 Hz), 7.43(2H, d, J=7.5 Hz), 7.51 (1H, t, J=2.1 Hz), 7.66 (1H, d, J=0.9 Hz), 8.08(1H, s), 8.18 (1H, d, J=9.6 Hz), 8.72 (1H, s), 8.87 (1H, s).

Example 143 Production ofN-[3-(imidazo[1,2-b]pyridazin-6-yloxy)phenyl]-N′-[3-(trifluoromethyl)phenyl]urea

To a solution of 3-(imidazo[1,2-b]pyridazin-6-yloxy)aniline (181 mg,0.80 mmol) and triethylamine (0.040 mL, 0.29 mmol) in tetrahydrofuran(10 mL) was added 3-(trifluoromethyl)phenyl isocyanate (0.154 mL, 1.12mmol), and the mixture was stirred at room temperature for 18 hr. Thereaction mixture was concentrated under reduced pressure, and theresidue was purified by silica gel column chromatography (ethylacetate/methanol=100/0→90/10) and precipitated from methanol to give thetitle compound (205 mg, 62%) as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 6.89-6.94 (1H, m), 7.12 (1H, d, J=9.8 Hz),7.26-7.34 (2H, m), 7.38 (1H, t, J=8.1 Hz), 7.47-7.60 (3H, m), 7.66 (1H,d, J=0.9 Hz), 7.99 (1H, s), 8.08 (1H, s), 8.18 (1H, d, J=9.8 Hz), 9.01(1H, s), 9.11 (1H, s).

Example 144 Production ofN-[3-(imidazo[1,2-b]pyridazin-6-yloxy)phenyl]-N′-[4-(trifluoromethyl)phenyl]urea

To a solution of 3-(imidazo[1,2-b]pyridazin-6-yloxy)aniline (113 mg,0.50 mmol) and triethylamine (0.040 mL, 0.29 mmol) in tetrahydrofuran(10 mL) was added 4-(trifluoromethyl)phenyl isocyanate (0.100 mL, 0.70mmol), and the mixture was stirred at room temperature for 18 hr. Thereaction mixture was concentrated under reduced pressure, and theresidue was precipitated from methanol to give the title compound (103mg, 50%) as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 6.86-6.94 (1H, m), 7.11 (1H, d, J=9.8 Hz),7.24-7.31 (1H, m), 7.38 (1H, t, J=8.2 Hz), 7.51 (1H, t, J=1.8 Hz),7.58-7.68 (5H, m), 8.08 (1H, s), 8.18 (1H, d, J=9.8 Hz), 9.00 (1H, s),9.16 (1H, s).

Example 145 Production ofN-[3-(imidazo[1,2-b]pyridazin-6-yloxy)phenyl]benzamide

To a solution of 3-(imidazo[1,2-b]pyridazin-6-yloxy)aniline (113 mg,0.50 mmol) in N-methylpyrrolidone (1.0 mL) was added benzoyl chloride(0.116 mL, 1.00 mmol), and the mixture was stirred at room temperaturefor 18 hr. The reaction mixture was diluted with 1N aqueous sodiumhydroxide solution, and extracted with ethyl acetate. The organic layerwas washed with 1N aqueous sodium hydroxide solution and saturatedbrine, and concentrated under reduced pressure. The residue was purifiedby silica gel column chromatography (ethyl acetate/methanol=100/0→75/25)and precipitated from ethyl acetate to give the title compound (122 mg,74%) as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 7.01-7.06 (1H, m), 7.14 (1H, d, J=9.8 Hz),7.45 (1H, t, J=8.2 Hz), 7.50-7.64 (3H, m), 7.66-7.71 (2H, m), 7.77 (1H,t, J=2.1 Hz), 7.92-7.97 (2H, m), 8.09 (1H, s), 8.19 (1H, d, J=9.8 Hz),10.39 (1H, s).

Example 146 Production ofN-[3-(imidazo[1,2-b]pyridazin-6-yloxy)phenyl]-3-(trifluoromethyl)benzamide

To a solution of 3-(imidazo[1,2-b]pyridazin-6-yloxy)aniline (113 mg,0.50 mmol) in N-methylpyrrolidone (1.0 mL) was added3-(trifluoromethyl)benzoyl chloride (0.151 mL, 1.00 mmol), and themixture was stirred at room temperature for 18 hr. The reaction mixturewas diluted with 1N aqueous sodium hydroxide solution, and extractedwith ethyl acetate. The organic layer was washed with 1N aqueous sodiumhydroxide solution and saturated brine, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/methanol=100/0→75/25), and precipitated from diisopropylether to give the title compound (195 mg, 98%) as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 7.05-7.10 (1H, m), 7.15 (1H, d, J=9.6 Hz),7.47 (1H, t, J=7.9 Hz), 7.67-7.71 (1H, m), 7.67 (1H, d, J=1.2 Hz), 7.75(1H, t, J=2.1 Hz), 7.79 (1H, t, J=7.8 Hz), 7.98 (1H, d, J=7.8 Hz), 8.09(1H, s), 8.20 (1H, d, J=9.6 Hz), 8.26 (1H, d, J=8.4 Hz), 8.29 (1H, s),10.61 (1H, s).

Example 147 Production ofN-{6-[(3-aminophenyl)sulfanyl]imidazo[1,2-b]pyridazin-2-yl}cyclopropanecarboxamide

A mixture ofN-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (500 mg,1.52 mmol), 3-aminobenzenethiol (381 mg, 3.04 mmol), potassium carbonate(630 mg, 4.56 mmol) and N,N-dimethylformamide (5.0 mL) was stirred at80° C. for 3 hr. The reaction mixture was diluted with water, andextracted with ethyl acetate. The organic layer was concentrated underreduced pressure, and the residue was purified by silica gel columnchromatography (ethyl acetate/methanol=100/0→80/20) and precipitatedfrom ethyl acetate to give the title compound (396 mg, 80%).

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.79-0.86 (4H, m), 1.89-1.99 (1H, m), 5.38(2H, s), 6.61-6.66 (1H, m), 6.66-6.70 (1H, m), 6.74 (1H, t, J=1.9 Hz),6.83 (1H, d, J=9.6 Hz), 7.11 (1H, t, J=7.8 Hz), 7.86 (1H, d, J=9.6 Hz),8.14 (1H, s), 11.16 (1H, s).

Example 148 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide

To a solution ofN-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(100 mg, 0.306 mmol) in N,N-dimethylacetamide (4.0 mL) was added asolution of 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (51 mg, 0.321mmol) in N,N-dimethylacetamide (1.0 mL) under ice-cooling, and themixture was stirred at room temperature for 30 min. Under ice-cooling,aqueous sodium hydrogencarbonate solution was added to the reactionmixture, and the mixture was extracted with ethyl acetate, washed withsaturated brine, dried over anhydrous magnesium sulfate, and filtrated.The solvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography (methanol/ethylacetate=0/100→5/95) and recrystallized from methanol/ethyl acetate togive the title compound (88.8 mg, 65%) as pale-yellow crystals. meltingpoint 237° C.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.75-0.90 (4H, m), 1.85-2.00 (1H, m), 2.19(3H, s), 3.97 (3H, s), 6.84 (1H, s), 7.07 (1H, d, J=9.3 Hz), 7.15-7.25(1H, m), 7.40 (1H, t, J=9.6 Hz), 7.50-7.60 (1H, m), 7.93 (1H, s), 8.04(1H, d, J=9.6 Hz), 10.10 (1H, s), 11.07 (1H, s).

Example 149 Production ofN-[3-({2-[(N,N-dimethylglycyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide

To a solution ofN-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]-N²,N²-dimethylglycinamide(196 mg, 0.6 mmol) in N-methylpyrrolidone (5.0 mL) was added1,3-dimethylpyrazole-5-carbonyl chloride (270 mg, 1.7 mmol), and themixture was stirred at room temperature for 5 hr. The reaction mixturewas diluted with 1N aqueous sodium hydroxide solution, and extractedwith ethyl acetate. The organic layer was concentrated under reducedpressure, and the residue was purified by silica gel columnchromatography (ethyl acetate/methanol=100/0→460/40) and precipitatedfrom ethyl acetate to give the title compound (131 mg, 49%) as a whitepowder. melting point 210° C.

¹H-NMR (DMSO-d₆, 300 MHz) δ 2.19 (3H, s), 2.27 (6H, s), 3.13 (2H, s),3.98 (3H, s), 6.83 (1H, s), 6.99-7.04 (1H, m), 7.09 (1H, d, J=9.6 Hz),7.43 (1H, t, J=8.1 Hz), 7.59-7.64 (1H, m), 7.68 (1H, t, J=2.1 Hz), 8.04(1H, s), 8.07 (1H, d, J=9.6 Hz), 10.25 (1H, s), 10.37 (1H, s).

Example 150 Production ofN-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}sulfanyl)phenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide

To a solution ofN-{6-[(3-aminophenyl)sulfanyl]imidazo[1,2-b]pyridazin-2-yl}cyclopropanecarboxamide(195 mg, 0.6 mmol) in N-methylpyrrolidone (3.0 mL) was added1,3-dimethylpyrazole-5-carbonyl chloride (159 mg, 1.0 mmol), and themixture was stirred at room temperature for 18 hr. The reaction mixturewas diluted with water, and extracted with ethyl acetate. The organiclayer was concentrated under reduced pressure, and the residue waspurified by silica gel column chromatography (ethylacetate/methanol=100/0→70/30) and precipitated from methanol to give thetitle compound (245 mg, 91%) as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.78-0.87 (4H, m), 1.89-1.99 (1H, m), 2.19(3H, s), 3.98 (3H, s), 6.82 (1H, s), 6.94 (1H, d, J=9.4 Hz), 7.31-7.36(1H, m), 7.47 (1H, t, J=7.8 Hz), 7.81-7.86 (1H, m), 7.90 (1H, dd, J=9.4,0.5 Hz), 7.99 (1H, t, J=1.9 Hz), 8.15 (1H, s), 10.25 (1H, s), 11.16 (1H,s). melting point 251° C.

Example 151 Production ofN-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]-N²,N²-dimethylglycinamide

A mixture ofN-(6-iodoimidazo[1,2-b]pyridazin-2-yl)-N²,N²-dimethylglycinamide (517mg, 1.5 mmol), 3-aminophenol (491 mg, 4.5 mmol), potassium carbonate(415 mg, 3.0 mmol) and N,N-dimethylformamide (3.0 mL) was stirred usinga microwave synthesizer at 180° C. for 40 min. The reaction mixture wasdiluted with water, and the precipitate was collected by filtration,washed with water, and dried under reduced pressure. The obtained solidwas washed with ethyl acetate to give the title compound (410 mg, 84%)as a brown powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 2.27 (6H, s), 3.13 (2H, s), 5.31 (2H, s),6.28-6.33 (1H, m), 6.36 (1H, t, J=2.1 Hz), 6.41-6.46 (1H, m), 6.98 (1H,d, J=9.6 Hz), 7.05 (1H, t, J=8.1 Hz), 8.01 (1H, d, J=9.6 Hz), 8.04 (1H,s), 10.35 (1H, s).

Example 152 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamidep-toluenesulfonate

ToN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide(2.00 g, 4.49 mmol) was added ethanol (80 mL), and the mixture washeated to 70° C. to give a uniform solution. p-Toluenesulfonic acidmonohydrate (0.90 g, 4.71 mmol) was added to the mixture, and themixture was naturally cooled to room temperature. The solvent wasevaporated under reduced pressure. To the obtained residue was addedhexane/ethanol (3/1, 40 mL), and the mixture was stirred at roomtemperature for 2 hr. The precipitated crystals were collected byfiltration, and washed with hexane/ethanol (3:1). The obtained crystalswere dissolved in ethanol (40 mL) by heating and the mixture wasnaturally cooled to room temperature. The precipitated crystals werecollected by filtration and washed with ethanol. The crystals were driedat 70° C. for 3 hr under reduced pressure to give the title compound(2.34 g, 84%) as white crystals.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.76-0.85 (4H, m), 1.87-1.97 (1H, m), 2.19(3H, s), 2.25 (3H, s), 2.29 (3H, s), 3.98 (3H, s), 6.82 (1H, s),7.09-7.15 (4H, m), 7.29 (1H, d, J=2.7 Hz), 7.35 (1H, d, J=8.4 Hz),7.47-7.51 (2H, m), 7.96 (1H, s), 8.08 (1H, d, J=9.6 Hz), 9.81 (1H, s),11.17 (1H, s).

Example 153 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamidebenzenesulfonate

UsingN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide(2.00 g, 4.49 mmol), ethanol (100 mL) and benzenesulfonic acidmonohydrate (0.83 g, 4.71 mmol), and in the same manner as in Example152, the title compound (2.02 g, 75%) was obtained as white crystals.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.78-0.84 (4H, m), 1.87-1.97 (1H, m), 2.19(3H, s), 2.25 (3H, s), 3.97 (3H, s), 6.80 (1H, s), 7.06-7.12 (2H, m),7.26-7.36 (5H, m), 7.57-7.61 (2H, m), 7.94 (1H, s), 8.05 (1H, d, J=9.6Hz), 9.79 (1H, s), 11.13 (1H, s).

elemental analysis (C₂₃H₂₃N₇O₃.C₆H₆O₃S)

Calculated: C, 57.70; H, 4.84; N, 16.24.

Found: C, 57.73; H, 4.80; N, 16.30.

Example 154 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamidemethanesulfonate

UsingN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide(2.00 g, 4.49 mmol), ethanol (80 mL) and methanesulfonic acid (0.34 mL,4.71 mmol), and in the same manner as in Example 152, the title compound(1.63 g, 67%) was obtained as white crystals.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.79-0.84 (4H, m), 1.87-1.97 (1H, m), 2.19(3H, s), 2.25 (3H, s), 2.40 (3H, s), 3.97 (3H, s), 6.81 (1H, s),7.07-7.12 (2H, m), 7.28 (1H, d, J=2.4 Hz), 7.34 (1H, d, J=8.7 Hz), 7.94(1H, s), 8.05 (1H, d, J=9.6 Hz), 9.80 (1H, s), 11.13 (1H, s).

elemental analysis (C₂₃H₂₃N₇O₃.CH₄O₃S)

Calculated: C, 53.23; H, 5.03; N, 18.10.

Found: C, 53.14; H, 5.05; N, 18.15.

Example 155 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide0.5 fumarate

ToN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide(2.00 g, 4.49 mmol) was added ethanol (100 mL) and the mixture washeated to 75° C. to give a uniform solution. Fumaric acid (0.55 g, 4.71mmol) was added to the mixture, and the mixture was naturally cooled toroom temperature and stirred for 3 hr. The precipitated crystals werecollected by filtration, and washed with ethanol. The obtained motherliquor was concentrated under reduced pressure, and ethanol (30 mL) wasadded to the obtained residue. The mixture was stirred at 60° C. for 30min. The mixture was cooled to room temperature and stood for 2 hr, andthe precipitated crystals were collected by filtration, and washed withethanol. The crystals were dried under reduced pressure at 70° C. for 3hr to give the title compound (1.73 g, 77%) as white crystals.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.78-0.83 (4H, m), 1.87-1.97 (1H, m), 2.20(3H, s), 2.25 (3H, s), 3.98 (3H, s), 6.63 (1H, s), 6.81 (1H, s), 7.05(1H, d, J=9.5 Hz), 7.10 (1H, dd, J=8.6, 2.6 Hz), 7.28 (1H, d, J=2.6 Hz),7.35 (1H, d, J=8.6 Hz), 7.94 (1H, s), 8.03 (1H, d, J=9.5 Hz), 9.80 (1H,s), 11.08 (1H, s).

elemental analysis (C₂₃H₂₃N₇O₃ 0.5C₄H₄O₄)

Calculated: C, 59.63; H, 5.00; N, 19.47.

Found: C, 59.58; H, 4.98; N, 19.47.

Example 156 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide0.5 succinate

UsingN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide(2.00 g, 4.49 mmol), ethanol (100 mL) and succinic acid (0.56 g, 4.71mmol), and in the same manner as in Example 155, the title compound(1.04 g, 46%) was obtained as white crystals.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.78-0.83 (4H, m), 1.87-1.96 (1H, m), 2.19(3H, s), 2.24 (3H, s), 2.49 (2H, s), 3.97 (3H, s), 6.80 (1H, s), 7.04(1H, d, J=9.6 Hz), 7.09 (1H, dd, J=8.3, 2.6 Hz), 7.27 (1H, d, J=2.6 Hz),7.34 (1H, d, J=8.3 Hz), 7.92 (1H, s), 8.02 (1H, d, J=9.6 Hz), 9.79 (1H,s), 11.06 (1H, s).

elemental analysis (C₂₃H₂₃N₇O₃.0.5C₄H₆O₄)

Calculated: C, 59.52; H, 5.19; N, 19.43.

Found: C, 59.36; H, 5.19; N, 19.37.

Example 157 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamidep-toluenesulfonate

ToN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide(225 mg, 0.5 mmol) were added tetrahydrofuran (5.0 mL) and ethanol (5.0mL), dissolved at 70° C., and p-toluenesulfonic acid monohydrate (95 mg,0.5 mmol) was added thereto. Ethanol (15.0 mL) was further added to themixture and insoluble material was filtered off. The filtrate wasconcentrated, ethyl acetate (10 mL) and ethanol (10 mL) were addedthereto, and the mixture was concentrated again. Ethyl acetate (10 mL)and ethanol (1.0 mL) were added thereto, and the mixture was stood atroom temperature for 6 hr. The precipitated crystals were collected byfiltration, washed successively with a small amount of ethanol anddiethyl ether, and dried under reduced pressure at 80° C. for 6 hr togive the title compound (285 mg, 92%) as white crystals.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.75-0.85 (4H, m), 1.85-1.95 (1H, m), 2.19(3H, s), 2.29 (3H, s), 3.98 (3H, s), 6.85 (1H, s), 7.08 (1H, d, J=9.6Hz), 7.11 (2H, d, J=7.7 Hz), 7.15-7.25 (1H, m), 7.40 (1H, t, J=9.6 Hz),7.47 (2H, d, J=7.7 Hz), 7.50-7.55 (1H, m), 7.94 (1H, s), 8.05 (1H, d,J=9.6 Hz), 10.10 (1H, s), 11.09 (1H, s).

Example 158 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamidebenzenesulfonate

ToN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide(1.00 g, 2.23 mmol) was added ethanol (50 mL), and the mixture wasstirred at 80° C. for 20 min. Benzenesulfonic acid monohydrate (0.41 g,2.33 mmol) was added to the mixture, and the mixture was further stirredfor 10 min. Insoluble material was removed by filtration, and themixture was naturally cooled to room temperature. The mixture was stoodat room temperature for 16 hr, and the precipitated crystals werecollected by filtration and washed with ethanol. The precipitatedcrystals were dried under reduced pressure at 80° C. for 6 hr to givethe title compound (1.17 g, 86%) as white crystals.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.78-0.84 (4H, m), 1.88-1.97 (1H, m), 2.19(3H, s), 3.98 (3H, s), 6.85 (1H, s), 7.10 (1H, d, J=9.6 Hz), 7.18-7.24(1H, m), 7.30-7.34 (3H, m), 7.41 (1H, t, J=9.5 Hz), 7.52-7.56 (1H, m),7.58-7.62 (2H, m), 7.95 (1H, s), 8.06 (1H, d, J=9.6 Hz), 10.10 (1H, s),11.11 (1H, s).

elemental analysis (C₂₂H₂₀FN₇O₃.C₆H₆O₃S)

Calculated: C, 55.35; H, 4.31; N, 16.14.

Found: C, 55.25; H, 4.33; N, 16.14.

Example 159 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamidemethanesulfonate

A solution ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide(1.00 g, 2.23 mmol) in ethanol (50 ml) was stirred at 70° C. for 20 min.Methanesulfonic acid (0.17 mL, 2.33 mmol) was added to the mixture, andthe mixture was further stirred for 10 min. The mixture was naturallycooled to room temperature, and the solvent was evaporated under reducedpressure. To the obtained residue was added hexane/ethanol (3:1, 40 mL),and the mixture was stirred at room temperature for 2 hr. Theprecipitated precipitate was collected by filtration, and washed withhexane/ethanol (3:1). The obtained precipitate was dissolved in ethanol(40 mL) by heating, and the mixture was naturally cooled to roomtemperature. The precipitated crystals were collected by filtration,ethyl acetate (20 mL) was added to the mixture, and the mixture wasstirred at 80° C. by heating. After cooling the mixture to roomtemperature, the precipitate was collected by filtration, washed withethyl acetate and dried under reduced pressure at 100° C. for 3 hr togive the title compound (0.32 g, 26%) as white crystals.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.77-0.83 (4H, m), 1.86-1.96 (1H, m), 2.19(3H, s), 2.33 (3H, s), 3.97 (3H, s), 6.84 (1H, s), 7.08 (1H, d, J=9.6Hz), 7.18-7.23 (1H, m), 7.39 (1H, t, J=9.6 Hz), 7.51-7.55 (1H, m), 7.93(1H, s), 8.04 (1H, d, J=9.6 Hz), 10.09 (1H, s), 11.08 (1H, s).

elemental analysis (C₂₂H₂₀FN₇O₃.CH₄O₃S)

Calculated: C, 50.64; H, 4.43; N, 17.97.

Found: C, 50.63; H, 4.38; N, 18.11.

Example 160 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide0.5 fumarate

ToN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide(2.00 g, 4.45 mmol) was added tetrahydrofuran (100 mL), and the mixturewas heated to 60° C. to give a uniform solution. Fumaric acid (0.54 g,4.67 mmol) was added to the mixture and the mixture was allowed to coolto room temperature. Insoluble material was filtrated, ethyl acetate (50mL) was added to the filtrate, and the solvent was evaporated to ¼ underreduced pressure. The precipitated crystals were collected byfiltration, washed with ethyl acetate and dried under reduced pressureat 80° C. for 3 hr to give the title compound (1.88 g, 83%) as whitecrystals.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.77-0.82 (4H, m), 1.87-1.96 (1H, m), 2.19(3H, s), 3.97 (3H, s), 6.61 (1H, s), 6.84 (1H, s), 7.07 (1H, d, J=9.6Hz), 7.18-7.23 (1H, m), 7.39 (1H, t, J=9.6 Hz), 7.51-7.54 (1H, m), 7.93(1H, s), 8.04 (1H, d, J=9.6 Hz), 10.09 (1H, s), 11.06 (1H, s).

elemental analysis (C₂₂H₂₀FN₇O₃.0.5C₄H₄O₄)

Calculated: C, 56.80; H, 4.37; N, 19.32.

Found: C, 56.73; H, 4.33; N, 19.24.

Example 161 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-1-ethyl-3-methyl-1H-pyrazole-4-carboxamide

To a solution of 1-ethyl-3-methyl-1H-pyrazole-4-carboxylic acid (2.00 g,13.0 mmol) and N,N-dimethylformamide (3 drops) in tetrahydrofuran (30mL) was added oxalyl chloride (2.23 mL, 26.0 mmol) with stirring underice-cooling, and the mixture was stirred at room temperature for 3 hr.The reaction mixture was concentrated under reduced pressure. Theresidue was dissolved in N,N-dimethylacetamide (20 mL) with stirringunder ice-cooling,N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(3.27 g, 10.0 mmol) was added thereto, and the mixture was stirred atroom temperature for 18 hr. The reaction mixture was diluted with 1Naqueous sodium hydroxide solution (50 ml) and extracted with a mixedsolvent of ethyl acetate/tetrahydrofuran (1:1, 80 mL, 40 mL×2). Theorganic layer was washed with water (10 mL×3), and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/methanol=100/0→70/30) and crystallizedfrom ethyl acetate to give the title compound (2.39 g, yield 52%) as awhite solid. melting point 199° C.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.75-0.85 (4H, m), 1.38 (3H, t, J=7.3 Hz),1.86-1.98 (1H, m), 2.33 (3H, s), 4.09 (2H, q, J=7.3 Hz), 7.06 (1H, d,J=9.6 Hz), 7.07-7.15 (1H, m), 7.36 (1H, dd, J=10.2, 9.0 Hz), 7.66 (1H,dd, J=6.3, 3.0 Hz), 7.94 (1H, s), 8.04 (1H, dd, J=9.6, 0.6 Hz), 8.39(1H, s), 9.54 (1H, s), 11.07 (1H, s).

Example 162 Production ofN-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]pyridine-2-carboxamide

To a solution ofN-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(155 mg, 0.50 mmol) in N-methylpyrrolidone (3 mL) was addedpyridine-2-carbonylchloride hydrochloride (107 mg, 0.60 mmol), and themixture was stirred at room temperature for 18 hr. A 5% aqueous sodiumhydrogencarbonate solution was added to the reaction mixture, and themixture was extracted with ethyl acetate. The organic layer wasconcentrated under reduced pressure, and the residue was purified bysilica gel column chromatography (ethyl acetate/methanol=100/0→80/20)and crystallized from ethyl acetate to give the title compound (131 mg,yield 63%) as a white solid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.73-0.87 (4H, m), 1.86-1.99 (1H, m), 7.02(1H, ddd, J=8.1, 2.5, 0.7 Hz), 7.07 (1H, d, J=9.3 Hz), 7.44 (1H, t,J=8.2 Hz), 7.68 (1H, ddd, J=7.3, 4.7, 1.3 Hz), 7.80-7.85 (1H, m), 7.90(1H, t, J=2.3 Hz), 7.99 (1H, s), 8.03-8.10 (2H, m), 8.12-8.18 (1H, m),8.72-8.76 (1H, m), 10.81 (1H, s), 11.09 (1H, s).

Example 163 Production ofN-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]isonicotinamide

UsingN-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(155 mg, 0.50 mmol), N-methylpyrrolidone (3 mL) andpyridine-4-carbonylchloride hydrochloride (107 mg, 0.60 mmol), and inthe same manner as in Example 162, the title compound (163 mg, yield78%) was obtained.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.75-0.85 (4H, m), 1.84-2.00 (1H, m),7.01-7.07 (1H, m), 7.08 (1H, d, J=9.6 Hz), 7.46 (1H, t, J=8.1 Hz),7.63-7.69 (1H, m), 7.73 (1H, t, J=2.1 Hz), 7.82-7.87 (2H, m), 7.98 (1H,s), 8.06 (1H, d, J=9.6 Hz), 8.76-8.81 (2H, m), 10.62 (1H, s), 11.09 (1H,s).

Example 164 Production ofN-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]nicotinamide

UsingN-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(155 mg, 0.50 mmol), N-methylpyrrolidone (3 mL) andpyridine-3-carbonylchloride hydrochloride (107 mg, 0.60 mmol), and inthe same manner as in Example 162, the title compound (89 mg, yield 43%)was obtained.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.74-0.87 (4H, m), 1.86-1.99 (1H, m), 7.03(1H, dd, J=7.8, 1.8 Hz), 7.08 (1H, d, J=9.6 Hz), 7.45 (1H, t, J=8.4 Hz),7.57 (1H, dd, J=7.8, 4.8 Hz), 7.66 (1H, d, J=8.1 Hz), 7.73 (1H, t, J=1.9Hz), 7.98 (1H, s), 8.06 (1H, d, J=9.6 Hz), 8.28 (1H, dt, J=7.9, 1.9 Hz),8.76 (1H, d, J=3.9 Hz), 9.09 (1H, s), 10.57 (1H, s), 11.09 (1H, s).

Example 165 Production ofN-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]benzamide

UsingN-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(155 mg, 0.50 mmol), N-methylpyrrolidone (3 mL) and benzoyl chloride(0.070 mL, 0.60 mmol), and in the same manner as in Example 162, thetitle compound (176 mg, yield 85%) was obtained. melting point 265° C.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.74-0.86 (4H, m), 1.87-1.99 (1H, m), 7.00(1H, ddd, J=8.1, 2.4, 0.8 Hz), 7.07 (1H, d, J=9.5 Hz), 7.43 (1H, t,J=8.1 Hz), 7.49-7.64 (3H, m), 7.68 (1H, d, J=8.4 Hz), 7.74 (1H, t, J=2.1Hz), 7.90-7.97 (2H, m), 7.98 (1H, s), 8.05 (1H, d, J=9.5 Hz), 10.38 (1H,s), 11.09 (1H, s).

Example 166 Production ofN-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-1,3-thiazole-2-carboxamide

UsingN-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(155 mg, 0.50 mmol), N-methylpyrrolidone (3 mL) and1,3-thiazole-2-carbonyl chloride (89 mg, 0.60 mmol), and in the samemanner as in Example 162, the title compound (136 mg, yield 65%) wasobtained.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.76-0.85 (4H, m), 1.86-1.99 (1H, m), 7.03(1H, ddd, J=8.2, 2.4, 1.0 Hz), 7.07 (1H, d, J=9.6 Hz), 7.44 (1H, t,J=8.1 Hz), 7.75-7.83 (2H, m), 7.98 (1H, s), 8.06 (1H, dd, J=9.6, 0.6Hz), 8.11 (1H, d, J=3.0 Hz), 8.15 (1H, d, J=3.0 Hz), 10.94 (1H, s),11.09 (1H, s).

Example 167 Production ofN-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-1,3-dimethyl-1H-pyrazole-4-carboxamide

To a suspension of 1,3-dimethyl-1H-pyrazole-4-carboxylic acid (140 mg,1.0 mmol) in dichloromethane (10 mL) were added N,N-dimethylformamide (2drops) then oxalyl chloride (0.171 mL, 2.0 mmol), and the mixture wasstirred at room temperature for 2 hr. The reaction mixture wasconcentrated under reduced pressure. The residue was diluted withN-methylpyrrolidone (5 mL),N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(155 mg, 0.50 mmol) was added thereto, and the mixture was stirred atroom temperature for 6 hr. To the reaction mixture was added 0.5Naqueous sodium hydroxide solution, and the mixture was extracted withethyl acetate. The organic layer was concentrated under reducedpressure, and the residue was purified by silica gel columnchromatography (ethyl acetate/methanol=100/0→70/30). The objectivefraction was concentrated under reduced pressure, and the residue waswashed with diisopropyl ether to give the title compound (126 mg, yield58%) as a white solid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.74-0.87 (4H, m), 1.86-1.99 (1H, m), 2.33(3H, s), 3.81 (3H, s), 6.93 (1H, dd, J=8.1, 1.8 Hz), 7.05 (1H, d, J=9.6Hz), 7.38 (1H, t, J=8.1 Hz), 7.55 (1H, d, J=8.1 Hz), 7.64 (1H, t, J=2.1Hz), 7.97 (1H, s), 8.05 (1H, d, J=9.6 Hz), 8.27 (1H, s), 9.78 (1H, s),11.09 (1H, s).

Example 168 Production ofN-[6-(3-amino-4-ethylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide

A mixture ofN-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (984 mg,3.0 mmol), 3-amino-4-ethylphenol (617 mg, 4.5 mmol), potassium carbonate(829 mg, 6.0 mmol) and N,N-dimethylformamide (9 mL) was stirred at 150°C. for 24 hr. The reaction mixture was diluted with water and extractedwith a mixed solvent of ethyl acetate/tetrahydrofuran (3:1). The organiclayer was concentrated under reduced pressure, and the residue waspurified by silica gel column chromatography (hexane/ethylacetate=50/50→0/100) and recrystallized from a mixed solvent of ethylacetate/diisopropyl ether to give the title compound (706 mg, yield 70%)as a khaki solid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.73-0.88 (4H, m), 1.14 (3H, t, J=7.4 Hz),1.85-2.00 (1H, m), 2.43 (2H, q, J=7.4 Hz), 5.07 (2H, s), 6.31 (1H, dd,J=8.1, 2.7 Hz), 6.42 (1H, d, J=2.7 Hz), 6.93 (1H, d, J=9.6 Hz), 6.95(1H, d, J=7.8 Hz), 7.97 (1H, s), 7.98 (1H, d, J=9.0 Hz), 11.05 (1H, s).

Example 169 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-ethylphenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide

To a solution ofN-[6-(3-amino-4-ethylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(202 mg, 0.60 mmol) in N-methylpyrrolidone (3 mL) was added1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (143 mg, 0.90 mmol), andthe mixture was stirred at room temperature for 8 hr. A 1N aqueoussodium hydroxide solution was added to the reaction mixture, and themixture was extracted with ethyl acetate. The organic layer wasconcentrated under reduced pressure, and the residue was purified bysilica gel column chromatography (ethyl acetate/methanol=100/0→80/20)and recrystallized from a mixed solvent of ethyl acetate/diisopropylether to give the title compound (167 mg, yield 61%) as a white solid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.76-0.84 (4H, m), 1.15 (3H, t, J=7.6 Hz),1.84-2.00 (1H, m), 2.19 (3H, s), 2.63 (2H, q, J=7.6 Hz), 3.97 (3H, s),6.80 (1H, s), 7.04 (1H, d, J=9.6 Hz), 7.15 (1H, dd, J=8.6, 2.6 Hz), 7.23(1H, d, J=2.6 Hz), 7.37 (1H, d, J=8.6 Hz), 7.94 (1H, s), 8.03 (1H, dd,J=9.6, 0.6 Hz), 9.82 (1H, s), 11.07 (1H, s).

Example 170 Production ofN-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-1H-pyrazole-5-carboxamide

To a mixture ofN-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(155 mg, 0.50 mmol), 1H-pyrazole-5-carboxylic acid (84 mg, 0.75 mmol),1-hydroxybenzotriazole (101 mg, 0.75 mmol) and N,N-dimethylformamide (5mL) were added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimidehydrochloride (192 mg, 1.0 mmol), triethylamine (0.279 mL, 2.0 mmol),and the mixture was stirred at room temperature for 18 hr. Water wasadded to the reaction mixture, and the mixture was extracted with amixed solvent of ethyl acetate/tetrahydrofuran. The organic layer wasconcentrated under reduced pressure, and the residue was purified bysilica gel column chromatography (ethyl acetate/methanol=100/0→70/30)and crystallized from ethyl acetate to give the title compound (43 mg,yield 21%) as a white solid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.73-0.88 (4H, m), 1.87-1.99 (1H, m), 6.76(1H, s), 6.95 (1H, dd, J=8.1, 1.8 Hz), 7.05 (1H, d, J=9.6 Hz), 7.39 (1H,t, J=8.4 Hz), 7.73 (1H, d, J=8.4 Hz), 7.79 (1H, s), 7.89 (1H, s), 7.98(1H, s), 8.04 (1H, d, J=9.6 Hz), 10.20 (1H, s), 11.07 (1H, s), 13.42(1H, s).

Example 171 Production ofN-{6-[(4-aminophenyl)thio]imidazo[1,2-b]pyridazin-2-yl}cyclopropanecarboxamide

To a solution ofN-(6-iodoimidazo[1,2-b]pyridazin-2-yl)-2-methylcyclopropanecarboxamide(2.0 g, 6.10 mmol) in N,N-dimethylformamide (20.0 mL) were addedpotassium carbonate (1.27 g, 9.14 mmol) and 4-aminothiophenol (0.92 g,7.31 mmol), and the mixture was stirred at 80° C. for 4 hr. Aftercooling the mixture to room temperature, water was added to the reactionmixture, and the mixture was extracted with ethylacetate/tetrahydrofuran, washed with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was collected by filtration and washed withethyl acetate to give the title compound (1.53 g, 77%) as browncrystals.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.78-0.85 (4H, m), 1.87-1.97 (1H, m), 5.68(2H, s), 6.60-6.67 (3H, m), 7.24-7.29 (2H, m), 7.78 (1H, d, J=9.5 Hz),8.06 (1H, s), 11.09 (1H, s).

Example 172 Production ofN-{6-[3-({[(phenylacetyl)amino]thiocarbonyl}amino)phenoxy]imidazo[1,2-b]pyridazin-2-yl}cyclopropanecarboxamide

To a solution of phenylacetyl chloride (155 mg, 1.0 mmol) inacetonitrile (20 mL) was added potassium thiocyanate (292 mg, 3.0 mmol),and the mixture was stirred at 60° C. for 3 hr and concentrated underreduced pressure. The residue was diluted with tetrahydrofuran (20 mL).N-[6-(3-Aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(155 mg, 0.50 mmol) was added to the mixture, and the mixture wasstirred at room temperature for 18 hr. The reaction mixture wasconcentrated under reduced pressure, water was added to the residue andthe mixture was extracted with ethyl acetate. The organic layer wasconcentrated under reduced pressure, and the residue was purified bysilica gel column chromatography (ethyl acetate/methanol=100/0→70/30)and precipitated from diisopropyl ether to give the title compound (142mg, yield 58%) as a white solid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.75-0.86 (4H, m), 1.86-1.98 (1H, m), 3.81(2H, s), 7.04 (1H, d, J=9.6 Hz), 7.10-7.19 (1H, m), 7.23-7.38 (5H, m),7.45 (2H, d, J=5.1 Hz), 7.74 (1H, s), 7.96 (1H, s), 8.03 (1H, d, J=9.6Hz), 11.07 (1H, s), 11.72 (1H, s), 12.46 (1H, s).

Example 173 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-1,3-dimethyl-1H-pyrazole-4-carboxamide

To a solution of 1,3-dimethyl-1H-pyrazole-4-carboxylic acid (140 mg, 1.0mmol) and N,N-dimethylformamide (2 drops) in tetrahydrofuran (10 mL) wasadded oxalyl chloride (0.171 mL, 2.0 mmol) with stirring underice-cooling, and the mixture was stirred at room temperature for 2 hr.The reaction mixture was concentrated under reduced pressure. Theresidue was dissolved in N-methylpyrrolidone (5 mL) with stirring underice-cooling,N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(164 mg, 0.50 mmol) was added, and the mixture was stirred at roomtemperature for 18 hr. The reaction mixture was diluted with ethylacetate (80 mL), and washed with 1N aqueous sodium hydroxide solution(10 mL) and water (10 mL×3). The organic layer was concentrated underreduced pressure, and the residue was purified by silica gel columnchromatography (ethyl acetate/methanol=100/0→70/30) and recrystallizedfrom ethyl acetate to give the title compound (88 mg, yield 39%) as awhite solid. melting point 205° C.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.73-0.88 (4H, m), 1.86-1.99 (1H, m), 2.32(3H, s), 3.81 (3H, s), 7.06 (1H, d, J=9.5 Hz), 7.06-7.14 (1H, m), 7.36(1H, dd, J=10.2, 9.0 Hz), 7.66 (1H, dd, J=6.4, 3.2 Hz), 7.94 (1H, s),8.03 (1H, d, J=9.5 Hz), 8.32 (1H, s), 9.53 (1H, s), 11.06 (1H, s).

Example 174 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-1-ethyl-1H-pyrazole-5-carboxamide

Using 1-ethyl-1H-pyrazole-5-carboxylic acid (140 mg, 1.0 mmol),N,N-dimethylformamide (2 drops), tetrahydrofuran (10 mL), oxalylchloride (0.172 mL, 2.0 mmol), N-methylpyrrolidone (5 mL) andN-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(164 mg, 0.50 mmol), and in the same manner as in Example 173, the titlecompound (119 mg, yield 53%) was obtained. melting point 209° C.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.75-0.86 (4H, m), 1.31 (3H, t, J=7.2 Hz),1.86-1.98 (1H, m), 4.50 (2H, q, J=7.2 Hz), 7.07 (1H, d, J=2.0 Hz), 7.08(1H, d, J=9.5 Hz), 7.22 (1H, ddd, J=9.0, 3.9, 3.0 Hz), 7.41 (1H, dd,J=10.2, 9.0 Hz), 7.52-7.57 (1H, m), 7.55 (1H, d, J=2.0 Hz), 7.94 (1H,s), 8.04 (1H, d, J=9.5 Hz), 10.19 (1H, s), 11.06 (1H, s).

Example 175 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-3-methylisoxazole-4-carboxamide

Using 3-methylisoxazole-4-carboxylic acid (127 mg, 1.0 mmol),N,N-dimethylformamide (2 drops), tetrahydrofuran (10 mL), oxalylchloride (0.172 mL, 2.0 mmol), N-methylpyrrolidone (5 mL) andN-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(164 mg, 0.50 mmol), and in the same manner as in Example 173, the titlecompound (143 mg, yield 65%) was obtained.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.75-0.86 (4H, m), 1.86-1.99 (1H, m), 2.40(3H, s), 7.07 (1H, d, J=9.3 Hz), 7.14-7.21 (1H, m), 7.40 (1H, dd,J=10.2, 9.0 Hz), 7.66 (1H, dd, J=6.3, 2.7 Hz), 7.94 (1H, s), 8.04 (1H,d, J=9.3 Hz), 9.48 (1H, s), 10.19 (1H, s), 11.06 (1H, s).

Example 176 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-5-methylisoxazole-4-carboxamide

UsingN-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(164 mg, 0.50 mmol), N-methylpyrrolidone (5 mL) and5-methylisoxazole-4-carbonyl chloride (146 mg, 1.00 mmol), and in thesame manner as in Example 162, the title compound (112 mg, yield 51%)was obtained.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.75-0.85 (4H, m), 1.86-1.98 (1H, m), 2.66(3H, s), 7.08 (1H, d, J=9.6 Hz), 7.19 (1H, ddd, J=9.0, 3.9, 3.0 Hz),7.41 (1H, dd, J=9.9, 9.0 Hz), 7.62 (1H, dd, J=6.3, 3.0 Hz), 7.94 (1H,s), 8.05 (1H, dd, J=9.6, 0.6 Hz), 9.06 (1H, s), 10.09 (1H, s), 11.08(1H, s).

Example 177 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-1,5-dimethyl-1H-pyrazole-4-carboxamide

Using 1,5-dimethyl-1H-pyrazole-4-carboxylic acid (140 mg, 1.0 mmol),N,N-dimethylformamide (2 drops), tetrahydrofuran (10 mL), oxalylchloride (0.172 mL, 2.0 mmol), N-methylpyrrolidone (5 mL) andN-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(164 mg, 0.50 mmol), and in the same manner as in Example 173, the titlecompound (106 mg, yield 47%) was obtained.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.75-0.86 (4H, m), 1.85-1.98 (1H, m), 2.48(3H, s), 3.75 (3H, s), 7.06 (1H, d, J=9.6 Hz), 7.13 (1H, ddd, J=8.9,3.8, 3.1 Hz), 7.36 (1H, dd, J=10.2, 9.0 Hz), 7.58 (1H, dd, J=6.3, 3.0Hz), 7.94 (1H, s), 8.04 (1H, s), 8.04 (1H, dd, J=9.6, 0.6 Hz), 9.63 (1H,s), 11.07 (1H, s).

Example 178 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-4-methyl-1,3-thiazole-5-carboxamide

Using 4-methyl-1,3-thiazole-5-carboxylic acid (143 mg, 1.0 mmol),N,N-dimethylformamide (2 drops), tetrahydrofuran (10 mL), oxalylchloride (0.172 mL, 2.0 mmol), N-methylpyrrolidone (5 mL) andN-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(164 mg, 0.50 mmol), and in the same manner as in Example 173, the titlecompound (179 mg, yield 79%) was obtained.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.73-0.86 (4H, m), 1.85-1.98 (1H, m), 2.63(3H, s), 7.08 (1H, d, J=9.5 Hz), 7.20 (1H, ddd, J=8.8, 3.7, 3.2 Hz),7.40 (1H, dd, J=9.9, 9.3 Hz), 7.59 (1H, dd, J=6.6, 3.0 Hz), 7.94 (1H,s), 8.04 (1H, d, J=9.5 Hz), 9.14 (1H, s), 10.13 (1H, s), 11.07 (1H, s).

Example 179 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-5-methyl-1,3-thiazole-4-carboxamide

Using 5-methyl-1,3-thiazole-4-carboxylic acid (143 mg, 1.0 mmol),N,N-dimethylformamide (2 drops), tetrahydrofuran (10 mL), oxalylchloride (0.172 mL, 2.0 mmol), N-methylpyrrolidone (5 mL) andN-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(164 mg, 0.50 mmol), and in the same manner as in Example 173, the titlecompound (107 mg, yield 47%) was obtained.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.75-0.85 (4H, m), 1.86-1.98 (1H, m), 2.78(3H, s), 7.08 (1H, d, J=9.6 Hz), 7.08-7.16 (1H, m), 7.42 (1H, dd,J=10.5, 9.0 Hz), 7.95 (1H, s), 8.00 (1H, dd, J=6.6, 3.0 Hz), 8.05 (1H,d, J=9.6 Hz), 9.02 (1H, s), 9.94 (1H, s), 11.08 (1H, s).

Example 180 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-3-methoxy-1-methyl-1H-pyrazole-5-carboxamide

Using 3-methoxy-1-methyl-1H-pyrazole-5-carboxylic acid (156 mg, 1.0mmol), N,N-dimethylformamide (2 drops), tetrahydrofuran (15 mL), oxalylchloride (0.172 mL, 2.0 mmol), N-methylpyrrolidone (5 mL) andN-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(164 mg, 0.50 mmol), and in the same manner as in Example 173, the titlecompound (85 mg, yield 36%) was obtained.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.76-0.84 (4H, m), 1.86-1.98 (1H, m), 3.80(3H, s), 3.92 (3H, s), 6.50 (1H, s), 7.08 (1H, d, J=9.6 Hz), 7.21 (1H,ddd, J=9.1, 4.0, 3.1 Hz), 7.40 (1H, dd, J=10.0, 9.1 Hz), 7.53 (1H, dd,J=6.3, 3.0 Hz), 7.94 (1H, s), 8.05 (1H, dd, J=9.6, 0.6 Hz), 10.14 (1H,s), 11.07 (1H, s).

Example 181 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-3-ethoxy-1-methyl-1H-pyrazole-5-carboxamide

Using 3-ethoxy-1-methyl-1H-pyrazole-5-carboxylic acid (170 mg, 1.0mmol), N,N-dimethylformamide (2 drops), tetrahydrofuran (15 mL), oxalylchloride (0.172 mL, 2.0 mmol), N-methylpyrrolidone (5 mL) andN-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(164 mg, 0.50 mmol), and in the same manner as in Example 173, the titlecompound (92 mg, yield 38%) was obtained.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.76-0.85 (4H, m), 1.30 (3H, t, J 7.0 Hz),1.85-1.99 (1H, m), 3.91 (3H, s), 4.12 (2H, q, J=7.0 Hz), 6.48 (1H, s),7.08 (1H, d, J=9.6 Hz), 7.18-7.25 (1H, m), 7.36-7.45 (1H, m), 7.53 (1H,dd, J=6.5, 3.1 Hz), 7.94 (1H, s), 8.05 (1H, dd, J=9.6, 0.4 Hz), 10.12(1H, s), 11.07 (1H, s).

Example 182 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-3-(2-methoxyethoxy)-1-methyl-1H-pyrazole-5-carboxamide

Using 3-(2-methoxyethoxy)-1-methyl-1H-pyrazole-5-carboxylic acid (200mg, 1.0 mmol), N,N-dimethylformamide (2 drops), tetrahydrofuran (15 mL),oxalyl chloride (0.172 mL, 2.0 mmol), N-methylpyrrolidone (5 mL) andN-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(164 mg, 0.50 mmol), and in the same manner as in Example 173, the titlecompound (128 mg, yield 50%) was obtained.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.76-0.85 (4H, m), 1.85-1.99 (1H, m), 3.29(3H, s), 3.59-3.67 (2H, m), 3.91 (3H, s), 4.15-4.23 (2H, m), 6.49 (1H,s), 7.08 (1H, d, J=9.5 Hz), 7.18-7.25 (1H, m), 7.41 (1H, dd, J=10.1, 9.1Hz), 7.53 (1H, dd, J=6.4, 2.9 Hz), 7.94 (1H, s), 8.05 (1H, dd, J=9.5,0.7 Hz), 10.14 (1H, s), 11.07 (1H, s).

Example 183 Production of6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-amine

A mixture of 6-iodoimidazo[1,2-b]pyridazin-2-amine (390 mg, 1.5 mmol),3-aminophenol (491 mg, 4.5 mmol), potassium carbonate (415 mg, 3.0 mmol)and N,N-dimethylformamide (3 mL) was stirred using a microwavesynthesizer at 180° C. for 40 min. The reaction mixture was diluted withwater and extracted with a mixed solvent of ethylacetate/tetrahydrofuran (1:1). The organic layer was concentrated underreduced pressure, and the residue was purified by silica gel columnchromatography (ethyl acetate/methanol=100/0→60/40). The objectivefraction was concentrated under reduced pressure, and the residue waspurified by NH silica gel column chromatography (ethylacetate/methanol=100/0→80/20) and precipitated from ethyl acetate togive the title compound (133 mg, yield 37%) as a purple solid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 5.27 (2H, s), 5.31 (2H, s), 6.23 (1H, ddd,J=7.8, 2.4, 0.9 Hz), 6.27 (1H, t, J=2.1 Hz), 6.38 (1H, ddd, J=8.1, 2.1,0.9 Hz), 6.69 (1H, d, J=9.3 Hz), 7.02 (1H, t, J=7.9 Hz), 7.14 (1H, s),7.68 (1H, dd, J=9.3, 0.6 Hz).

Example 184 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]-5-methylisoxazole-4-carboxamide

UsingN-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(162 mg, 0.50 mmol), N-methylpyrrolidone (5 mL) and5-methylisoxazole-4-carbonyl chloride (146 mg, 1.0 mmol), and in thesame manner as in Example 162, the title compound (174 mg, yield 80%)was obtained.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.73-0.88 (4H, m), 1.86-1.99 (1H, m), 2.26(3H, s), 2.66 (3H, s), 7.04 (1H, d, J=9.6 Hz), 7.09 (1H, dd, J=8.6, 2.6Hz), 7.29 (1H, d, J=2.6 Hz), 7.35 (1H, d, J=8.6 Hz), 7.93 (1H, s), 8.03(1H, dd, J=9.6, 0.4 Hz), 9.02 (1H, s), 9.75 (1H, s), 11.07 (1H, s).

Example 185 Production ofN-[6-(3-amino-4-bromophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide

A mixture ofN-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (3.28 g,10 mmol), 3-amino-4-bromophenol (2.82 g, 15 mmol), potassium carbonate(2.76 g, 20 mmol) and N,N-dimethylformamide (20 mL) was stirred at 110°C. for 24 hr, then at 150° C. for 24 hr. The reaction mixture wasdiluted with water and extracted with a mixed solvent of ethylacetate/tetrahydrofuran (1:1). The organic layer was concentrated underreduced pressure, and the residue was purified by silica gel columnchromatography (hexane/ethyl acetate=50/50→40/100) and recrystallizedfrom ethyl acetate to give the title compound (1.85 g, yield 48%) as apale-yellow solid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.74-0.88 (4H, m), 1.86-1.98 (1H, m), 5.51(2H, s), 6.35 (1H, dd, J=8.6, 2.8 Hz), 6.62 (1H, d, J=2.8 Hz), 7.01 (1H,d, J=9.6 Hz), 7.37 (1H, d, J=8.6 Hz), 7.99 (1H, s), 8.02 (1H, d, J=9.6Hz), 11.08 (1H, s).

Example 186 Production ofN-[2-bromo-5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide

To a solution ofN-[6-(3-amino-4-bromophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(582 mg, 1.50 mmol) in N-methylpyrrolidone (5 mL) was added1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (310 mg, 1.95 mmol), andthe mixture was stirred at room temperature for 18 hr. A 5% aqueoussodium hydrogencarbonate solution was added to the reaction mixture, andthe mixture was extracted with a mixed solvent of ethylacetate/tetrahydrofuran (1:1). The organic layer was washed with water,dried over anhydrous sodium sulfate, filtrated, and concentrated underreduced pressure. The residue was suspended in ethyl acetate, and themixture was stirred with heating under reflux for 15 min. After allowingthe reaction mixture to cool to room temperature, the precipitate wascollected by filtration, washed with ethyl acetate, and dried underreduced pressure to give the title compound (658 mg, yield 86%) as acream solid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.73-0.88 (4H, m), 1.86-1.98 (1H, m), 2.20(3H, s), 3.98 (3H, s), 6.83 (1H, s), 7.10 (1H, d, J=9.6 Hz), 7.20 (1H,dd, J=8.9, 2.9 Hz), 7.51 (1H, dd, J=2.9 Hz), 7.79 (1H, d, J=8.9 Hz),7.95 (1H, s), 8.06 (1H, dd, J=9.6, 0.6 Hz), 9.97 (1H, s), 11.09 (1H, s).

Example 187 Production ofN-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-3-methylpyridine-2-carboxamide

To a solution ofN-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(100 mg, 0.323 mmol), 3-methylpyridine-2-carboxylic acid (66 mg, 0.485mmol) and 1-hydroxybenzotriazole (71 mg, 0.522 mmol) inN,N-dimethylformamide (4.0 mL) were added triethylamine (0.08 mL, 0.549mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride(99 mg, 0.517 mmol) under ice-cooling, and the mixture was stirred atroom temperature for 20 hr. Under ice-cooling, aqueous sodiumhydrogencarbonate solution was added to the reaction mixture, and themixture was extracted with ethyl acetate. The extract was washed withsaturated brine, dried over anhydrous magnesium sulfate, and filtrated.The solvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography (ethylacetate/hexane=80/20→100/0) and recrystallized from ethylacetate/methanol to give the title compound (98 mg, 71%) as colorlesscrystals.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.70-0.90 (4H, m), 1.85-2.00 (1H, m), 2.55(3H, s), 6.95-7.05 (1H, m), 7.05 (1H, d, J=9.6 Hz), 7.41 (1H, t, J=7.8Hz), 7.45-7.55 (1H, m), 7.71 (1H, d, J=8.4 Hz), 7.75-7.85 (2H, m), 8.04(1H, d, J=8.7 Hz), 8.50-8.55 (1H, m), 10.68 (1H, s), 11.07 (1H, s).

Example 188 Production ofN-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-6-methylpyridine-2-carboxamide

UsingN-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(100 mg, 0.323 mmol), 6-methylpyridine-2-carboxylic acid (66 mg, 0.485mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (99mg, 0.517 mmol), 1-hydroxybenzotriazole (71 mg, 0.522 mmol),triethylamine (0.08 mL, 0.549 mmol) and N,N-dimethylformamide (4.0 mL),and by a reaction in the same manner as in Example 187, the titlecompound (100 mg, 72%) was obtained as colorless crystals.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.75-0.85 (4H, m), 1.85-1.95 (1H, m), 2.62(3H, s), 7.00-7.05 (1H, m), 7.07 (1H, d, J=9.6 Hz), 7.44 (1H, t, J=7.8Hz), 7.50-7.55 (1H, m), 7.79 (1H, d, J=7.8 Hz), 7.85-7.95 (3H, m), 8.05(1H, d, J=9.6 Hz), 7.97 (1H, s), 10.56 (1H, s), 11.08 (1H, s).

Example 189 Production ofN-[6-(3{[(methylsulfonyl)acetyl]amino}phenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide

UsingN-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(100 mg, 0.323 mmol), (methylsulfonyl)acetic acid (67 mg, 0.485 mmol),1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (99 mg,0.517 mmol), 1-hydroxybenzotriazole (71 mg, 0.522 mmol), triethylamine(0.08 mL, 0.549 mmol) and N,N-dimethylformamide (4.0 mL), and by areaction in the same manner as in Example 187, the title compound (87mg, 63%) was obtained as pale-yellow crystals.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.75-0.85 (4H, m), 1.90-2.00 (1H, m), 3.15(3H, s), 4.27 (2H, s), 6.95-7.05 (1H, m), 7.05 (1H, d, J=9.3 Hz),7.35-7.45 (2H, m), 7.57 (1H, s), 7.95 (1H, s), 8.04 (1H, d, J=9.3 Hz),10.58 (1H, s), 11.08 (1H, s).

Example 190 Production ofN-(6-{3-[(3-hydroxy-3-methylbutanoyl)amino]phenoxy}imidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide

UsingN-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(100 mg, 0.323 mmol), 3-hydroxy-3-methylbutanoic acid (57 mg, 0.485mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (99mg, 0.517 mmol), 1-hydroxybenzotriazole (71 mg, 0.522 mmol),triethylamine (0.08 mL, 0.549 mmol) and N,N-dimethylformamide (4.0 mL),and by a reaction in the same manner as in Example 187, the titlecompound (22 mg, 16%) was obtained as pale-yellow crystals.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.75-0.85 (4H, m), 1.21 (6H, s), 1.90-2.00(1H, m), 2.41 (2H, s), 4.69 (1H, s), 6.90-6.95 (1H, m), 7.03 (1H, d,J=9.4 Hz), 7.30-7.45 (2H, m), 7.55-7.60 (1H, m), 7.96 (1H, s), 8.04 (1H,d, J=9.4 Hz), 9.97 (1H, s), 11.09 (1H, s).

Example 191 Production ofN-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]-2-cyclopropylacetamide

A mixture of2-cyclopropyl-N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)acetamide (501 mg,1.46 mmol), 3-aminophenol (479 mg, 4.39 mmol), potassium carbonate (807mg, 5.84 mmol) and N,N-dimethylformamide (5 mL) was stirred at 120° C.for 12 hr. Tetrahydrofuran/ethyl acetate and saturated brine were addedto the reaction mixture, and insoluble material was filtered off. Thefiltrate was extracted with ethyl acetate, dried over anhydrousmagnesium sulfate, and filtrated. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography (hexane/ethyl acetate=20/80→0/100) to give the titlecompound (156 mg, 33%) as a pale-yellow powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.10-0.25 (2H, m), 0.45-0.55 (2H, m),1.00-1.10 (1H, m), 2.25 (2H, d, J=7.2 Hz), 5.31 (2H, s), 6.30 (1H, d,J=8.1 Hz), 6.35 (1H, s), 6.43 (1H, d, J=8.1 Hz), 6.95 (1H, d, J=9.6 Hz),7.05 (1H, t, J=8.1 Hz), 7.99 (1H, d, J=9.6 Hz), 8.03 (1H, s), 10.70 (1H,s).

Example 192 Production ofN-[5-({2-[(cyclopropylacetyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide

Using 2-cyclopropyl-N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)acetamide (171mg, 0.5 mmol),N-(2-fluoro-5-hydroxyphenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide (150mg, 0.6 mmol), potassium carbonate (104 mg, 0.75 mmol) andN,N-dimethylformamide (4 mL), and by a reaction in the same manner as inExample 191, the title compound (53 mg, 23%) was obtained as pale-pinkcrystals.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.10-0.20 (2H, m), 0.40-0.50 (2H, m),1.00-1.15 (1H, m), 2.19 (3H, s), 2.24 (2H, d, J=7.2 Hz), 3.97 (3H, s),6.84 (1H, s), 7.07 (1H, d, J=9.6 Hz), 7.15-7.25 (1H, m), 7.40 (1H, t,J=9.6 Hz), 7.50-7.60 (1H, m), 7.98 (1H, s), 8.03 (1H, d, J=9.6 Hz),10.09 (1H, s), 10.68 (1H, s).

Example 193 Production ofN-[3-({2-[(cyclopropylacetyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide

UsingN-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]-2-cyclopropylacetamide(100 mg, 0.309 mmol), 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (64mg, 0.404 mmol) and N,N-dimethylacetamide (5.0 mL), and by a reaction inthe same manner as in Example 148, the title compound (85 mg, 62%) wasobtained as colorless crystals.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.15-0.25 (2H, m), 0.40-0.50 (2H, m),1.00-1.15 (1H, m), 2.19 (3H, s), 2.25 (2H, d, J=6.9 Hz), 3.97 (3H, s),6.82 (1H, s), 7.00 (1H, d, J=8.1 Hz), 7.05 (1H, d, J=9.6 Hz), 7.42 (1H,t, J=8.1 Hz), 7.60 (1H, d, J=8.1 Hz), 7.67 (1H, s), 8.02 (1H, s),8.05-8.10 (1H, m), 10.23 (1H, s), 10.70 (1H, s).

Example 194 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]-4-methylpyridine-2-carboxamide

UsingN-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(120 mg, 0.371 mmol), 4-methylpyridine-2-carboxylic acid (76 mg, 0.557mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride(114 mg, 0.594 mmol), 1-hydroxybenzotriazole (81 mg, 0.600 mmol),triethylamine (0.09 mL, 0.631 mmol) and N,N-dimethylformamide (6.0 mL),and by a reaction in the same manner as in Example 187, the titlecompound (40 mg, 24%) was obtained as pale-yellow crystals.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.75-0.85 (4H, m), 1.85-2.00 (1H, m), 2.35(3H, s), 2.44 (3H, s), 7.00-7.10 (2H, m), 7.34 (1H, d, J=8.7 Hz),7.50-7.55 (1H, m), 7.85-8.00 (3H, m), 8.02 (1H, d, J=9.3 Hz), 8.58 (1H,d, J=4.8 Hz), 10.31 (1H, s), 11.07 (1H, s).

Example 195 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]-2-methylnicotinamide

UsingN-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(120 mg, 0.371 mmol), 2-methylpyridine-3-carboxylic acid (76 mg, 0.557mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride(114 mg, 0.594 mmol), 1-hydroxybenzotriazole (81 mg, 0.600 mmol),triethylamine (0.09 mL, 0.631 mmol) and N,N-dimethylformamide (6.0 mL),and by a reaction in the same manner as in Example 187, the titlecompound (52 mg, 31%) was obtained as pale-pink crystals.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.75-0.85 (4H, m), 1.85-1.95 (1H, m), 2.30(3H, s), 2.59 (3H, s), 7.00-7.10 (2H, m), 7.30-7.35 (2H, m), 7.40-7.45(1H, m), 7.85-7.90 (1H, m), 7.93 (1H, s), 8.02 (1H, d, J=9.6 Hz), 8.54(1H, d, J=3.0 Hz), 9.98 (1H, s), 11.06 (1H, s).

Example 196 Production ofN-(6-{4-methyl-3-[(pyridin-2-ylacetyl)amino]phenoxy}imidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide

To a solution ofN-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(120 mg, 0.371 mmol) and pyridin-2-ylacetic acid hydrochloride (129 mg,0.742 mmol) in N,N-dimethylformamide (4.0 mL) were added dropwisetriethylamine (0.21 mL, 1.484 mmol) and diethyl cyanophosphate (0.12 mL,0.816 mmol) under ice-cooling, and the mixture was stirred at roomtemperature for 3 hr. Under ice-cooling, aqueous sodiumhydrogencarbonate solution was added to the reaction mixture, and themixture was extracted with ethyl acetate. The extract was washed withsaturated brine, dried over anhydrous magnesium sulfate, and filtrated.The solvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography (ethylacetate/methanol=100/0→95/5) and recrystallized from ethyl acetate togive the title compound (67 mg, 41%) as pale-yellow crystals.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.75-0.85 (4H, m), 1.90-2.00 (1H, m), 2.25(3H, s), 3.90 (2H, s), 6.90-7.00 (1H, m), 7.00 (1H, d, J=9.6 Hz),7.20-7.30 (2H, m), 7.40 (1H, t, J=7.8 Hz), 7.50-7.55 (1H, m), 7.70-7.80(1H, m), 7.91 (1H, s), 7.99 (1H, d, J=9.6 Hz), 8.50-8.55 (1H, m), 9.79(1H, s), 11.05 (1H, s).

Example 197 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-3-methylpyridine-2-carboxamide

UsingN-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(200 mg, 0.611 mmol), 3-methylpyridine-2-carboxylic acid (126 mg, 0.917mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride(187 mg, 0.978 mmol), 1-hydroxybenzotriazole (133 mg, 0.988 mmol),triethylamine (0.14 mL, 1.039 mmol) and N,N-dimethylformamide (6.0 mL),and by a reaction in the same manner as in Example 187, the titlecompound (128 mg, 47%) was obtained as colorless crystals.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.75-0.90 (4H, m), 1.85-2.00 (1H, m), 2.63(3H, s), 7.05-7.20 (2H, m), 7.35-7.50 (1H, m), 7.50-7.60 (1H, m), 7.84(1H, d, J=7.5 Hz), 7.94 (1H, s), 8.04 (1H, d, J=9.9 Hz), 8.10-8.15 (1H,m), 8.55-8.60 (1H, m), 10.57 (1H, s), 11.07 (1H, s).

Example 198 Production ofN-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]-2-cyclopropylacetamide

Using 2-cyclopropyl-N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)acetamide (300mg, 0.877 mmol), 3-amino-4-methylphenol (216 mg, 1.754 mmol), potassiumcarbonate (182 mg, 1.316 mmol) and N,N-dimethylformamide (3 mL), and bya reaction in the same manner as in Example 191, the title compound (138mg, 47%) was obtained as a orange powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.15-0.25 (2H, m), 0.40-0.50 (2H, m),1.00-1.10 (1H, m), 2.05 (3H, s), 2.25 (2H, d, J=6.9 Hz), 5.07 (2H, s),6.28 (1H, d, J=7.5 Hz), 6.42 (1H, s), 6.90-7.00 (2H, m), 7.97 (1H, d,J=9.6 Hz), 8.01 (1H, s), 10.68 (1H, s).

Example 199 Production ofN-[5-({2-[(cyclopropylacetyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide

UsingN-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]-2-cyclopropylacetamide(120 mg, 0.356 mmol), 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (59mg, 0.374 mmol) and N,N-dimethylacetamide (4.0 mL), and by a reaction inthe same manner as in Example 148, the title compound (99 mg, 61%) wasobtained as a pale-yellow powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.15-0.25 (2H, m), 0.40-0.50 (2H, m),1.00-1.15 (1H, m), 2.19 (3H, s), 2.25-2.30 (5H, m), 3.97 (3H, s), 6.80(1H, s), 7.04 (1H, d, J=9.8 Hz), 7.05-7.15 (1H, m), 7.25-7.30 (1H, m),7.34 (1H, d, J=8.1 Hz), 7.98 (1H, s), 8.02 (1H, d, J=9.8 Hz), 9.80 (1H,s), 10.68 (1H, s).

Example 200 Production ofN-[6-(4-fluoro-3-{[(methoxyamino)carbonyl]amino}phenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide

A solution of 1,1′-carbonyldiimidazole (297 mg, 1.833 mmol),O-methylhydroxyammonium chloride (153 mg, 1.833 mmol) and triethylamine(0.25 mL, 1.833 mmol) in N,N-dimethylformamide (4.0 mL) was stirred atroom temperature for 30 min. A solution ofN-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cycloprcpanecarboxamide(200 mg, 0.611 mmol) in N,N-dimethylformamide (2.0 mL) was further addedto the mixture, and the mixture was stirred at room temperature for 2days. Under ice-cooling, aqueous sodium hydrogencarbonate solution wasadded to the reaction mixture, and the mixture was extracted with ethylacetate. The extract was washed with saturated brine, dried overanhydrous magnesium sulfate, and filtrated. The solvent was evaporatedunder reduced pressure, and the residue was recrystallized fromtetrahydrofuran/ethanol to give the title compound (67 mg, 27%) ascolorless crystals.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.75-0.85 (4H, m), 1.85-2.00 (1H, m), 3.63(3H, s), 6.95-7.05 (1H, m), 7.05 (1H, d, J=9.3 Hz), 7.25-7.40 (1H, m),7.70-7.75 (1H, m), 7.93 (1H, s), 8.03 (1H, d, J=9.3 Hz), 8.55 (1H, s),9.76 (1H, s), 11.07 (1H, s).

Example 201 Production ofN-[6-(4-fluoro-3-{[(isobutoxyamino)carbonyl]amino}phenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide

UsingN-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(200 mg, 0.611 mmol), 1,1′-carbonyldiimidazole (297 mg, 1.833 mmol),1-(aminooxy)-2-methylpropane hydrochloride (230 mg, 1.833 mmol),triethylamine (0.25 mL, 1.833 mmol) and N,N-dimethylformamide (6.0 mL),and by a reaction in the same manner as in Example 200, the titlecompound (170 mg, 63%) was obtained as colorless crystals.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.75-0.85 (4H, m), 0.92 (6H, d, J=6.9 Hz),1.85-2.00 (1H, m), 3.58 (2H, d, J=6.9 Hz), 6.95-7.05 (1H, m), 7.04 (1H,d, J=9.9 Hz), 7.33 (1H, t, J=9.9 Hz), 7.80-7.90 (1H, m), 7.92 (1H, s),8.02 (1H, d, J=9.9 Hz), 8.31 (1H, s), 9.80 (1H, s), 11.06 (1H, s).

Example 202 Production ofN-{6-[4-fluoro-3-({[(5-methylisoxazol-3-yl)amino]carbonyl}amino)phenoxy]imidazo[1,2-b]pyridazin-2-yl}cyclopropanecarboxamide

To a solution of pyridine (475 mg, 6 mmol) and 3-amino-5-methylisoxazole(147 mg, 1.5 mmol) in N,N-dimethylformamide (2.0 mL) was added dropwisea solution of phenyl chlorocarbonate (235 mg, 1.5 mmol) inN,N-dimethylformamide (2.0 mL) under ice-cooling. After the mixture wasstirred at room temperature for 2 hr,N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(327 mg, 1.0 mmol) was added to the mixture, and the mixture was stirredat 80° C. for 15 hr and at 100° C. for 2 hr. Under ice-cooling, aqueoussodium hydrogencarbonate solution was added to the reaction mixture, andthe mixture was extracted with ethyl acetate. The extract was washedwith saturated brine, dried over anhydrous magnesium sulfate, andfiltrated. The solvent was evaporated under reduced pressure, and theresidue was purified by basic silica gel column chromatography (ethylacetate/hexane=80/20→100/0) and recrystallized fromtetrahydrofuran/ethanol to give the title compound (101 mg, 22%) ascolorless crystals.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.75-0.90 (4H, m), 1.85-2.00 (1H, m), 2.34(3H, s), 6.48 (1H, s), 6.90-7.00 (1H, m), 7.04 (1H, d, J=9.3 Hz), 7.35(1H, t, J=9.9 Hz), 7.90 (1H, s), 8.03 (1H, d, J=9.3 Hz), 9.00 (1H, brs), 9.85 (1H, br s), 11.06 (1H, s).

Example 203 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-1,4-dimethyl-1H-pyrazole-3-carboxamide

To a suspension of 1,4-dimethyl-1H-pyrazole-3-carboxylic acid (151 mg,1.08 mmol) in tetrahydrofuran (2.0 mL) were added N,N-dimethylformamide(1 drop) and thionyl chloride (0.08 mL, 1.1 mmol), and the mixture wasstirred at room temperature for 50 min. The reaction mixture wasconcentrated under reduced pressure and dissolved inN,N-dimethylacetamide (2.0 mL). On the other hand, to a solution ofN-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(327 mg, 1.0 mmol) in N,N-dimethylacetamide (6.0 mL) was added dropwisethe above-mentioned solution under ice-cooling, and the mixture wasstirred at room temperature for 2 hr. Under ice-cooling, aqueous sodiumhydrogencarbonate solution was added to the reaction mixture, and themixture was extracted with ethyl acetate. The extract was washed withsaturated brine, dried over anhydrous magnesium sulfate, and filtrated.The solvent was evaporated under reduced pressure, and the residue waspurified by basic silica gel column chromatography (ethylacetate/hexane=80/20→100/0) and recrystallized fromtetrahydrofuran/ethanol to give the title compound (283 mg, 63%) aspale-yellow crystals.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.75-0.85 (4H, m), 1.85-2.00 (1H, m), 2.21(3H, s), 3.89 (3H, s), 7.05-7.15 (2H, m), 7.38 (1H, t, J=9.6 Hz), 7.65(1H, s), 7.90-8.00 (2H, m), 8.03 (1H, d, J=9.6 Hz), 9.40 (1H, s), 11.06(1H, s).

Example 204 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-1,4-dimethyl-1H-pyrazole-5-carboxamide

UsingN-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(327 mg, 1.0 mmol), 1,4-dimethyl-1H-pyrazole-5-carboxylic acid (154 mg,1.1 mmol), tetrahydrofuran (2.0 mL), N,N-dimethylformamide (1 drop),thionyl chloride (0.08 mL, 1.1 mmol) and N,N-dimethylacetamide (6.0 mL),and by a reaction in the same manner as in Example 203, the titlecompound (300 mg, 67%) was obtained as pale-yellow crystals.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.75-0.85 (4H, m), 1.85-2.00 (1H, m), 2.19(3H, s), 3.90 (3H, s), 7.07 (1H, d, J=9.6 Hz), 7.15-7.25 (1H, m), 7.33(1H, s), 7.40 (1H, t, J=9.6 Hz), 7.75-7.80 (1H, m), 7.93 (1H, s), 8.04(1H, d, J=9.6 Hz), 10.06 (1H, s), 11.06 (1H, s).

Example 205 Production ofN-(2-fluoro-5-{[2-(isobutyrylamino)imidazo[1,2-b]pyridazin-6-yl]oxy}phenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide

UsingN-{5-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]-2-fluorophenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamidehydrochloride (200 mg, 0.48 mmol), 2-methylpropanoyl chloride (53 mg,0.50 mmol) and N,N-dimethylacetamide (5.0 mL), and by a reaction in thesame manner as in Example 148, the title compound (98 mg, 45%) wasobtained as pale-blue crystals.

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.08 (6H, d, J=6.9 Hz), 2.19 (3H, s),2.65-2.75 (1H, m), 3.97 (3H, s), 6.84 (1H, s), 7.06 (1H, d, J=9.6 Hz),7.15-7.25 (1H, m), 7.40 (1H, t, J=9.6 Hz), 7.50-7.60 (1H, m), 7.98 (1H,s), 8.03 (1H, d, J=9.6 Hz), 10.09 (1H, s), 10.72 (1H, s).

Example 206 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]pyrazine-2-carboxamide

Using a solution ofN-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(327 mg, 1.0 mmol) and 2-pyrazinecarbonylchloride (171 mg, 1.2 mmol) inN,N-dimethylacetamide (6.0 mL), and by a reaction in the same manner asin Example 148, the title compound (113 mg, 26%) was obtained ascolorless crystals.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.70-0.85 (4H, m), 1.85-2.00 (1H, m), 7.09(1H, d, J=9.6 Hz), 7.15-7.25 (1H, m), 7.44 (1H, t, J=9.6 Hz), 7.90-8.00(2H, m), 8.05 (1H, d, J=9.6 Hz), 8.83 (1H, s), 8.96 (1H, s), 9.28 (1H,s), 10.44 (1H, s), 11.07 (1H, s).

Example 207 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-1-methyl-1H-pyrrole-2-carboxamide

UsingN-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(327 mg, 1.0 mmol), 1-methyl-1H-pyrrole-2-carbonyl chloride (151 mg,1.05 mmol) and N,N-dimethylacetamide (6.0 mL), and by a reaction in thesame manner as in Example 148, the title compound (268 mg, 62%) wasobtained as colorless crystals.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.75-0.85 (4H, m), 1.90-2.00 (1H, m), 3.84(3H, s), 6.05-6.10 (1H, m), 7.00-7.20 (4H, m), 7.35 (1H, t, J=9.6 Hz),7.50-7.60 (1H, m), 7.93 (1H, s), 8.03 (1H, d, J=9.6 Hz), 9.63 (1H, s),11.06 (1H, s).

Example 208 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-3-ethyl-1-methyl-1H-pyrazole-5-carboxamide

UsingN-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(327 mg, 1.0 mmol), 3-ethyl-1-methyl-1H-pyrazole-5-carboxylic acid (170mg, 1.1 mmol) tetrahydrofuran (2.0 mL), N,N-dimethylformamide (1 drop),thionyl chloride (0.08 mL, 1.1 mmol) and N,N-dimethylacetamide (6.0 mL),and by a reaction in the same manner as in Example 203, the titlecompound (256 mg, 55%) was obtained as colorless crystals. melting point236° C.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.75-0.85 (4H, m), 1.19 (3H, t, J=7.5 Hz),1.90-2.00 (1H, m), 2.56 (2H, q, J=7.5 Hz), 3.98 (3H, s), 6.89 (1H, s),7.06 (1H, d, J=9.6 Hz), 7.15-7.25 (1H, m), 7.39 (1H, t, J=9.6 Hz),7.50-7.55 (1H, m), 7.93 (1H, s), 8.04 (1H, d, J=9.6 Hz), 10.10 (1H, s),11.07 (1H, s).

Example 209 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]-1,4-dimethyl-1H-pyrazole-3-carboxamide

UsingN-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(323 mg, 1.0 mmol), 1,4-dimethyl-1H-pyrazole-3-carboxylic acid (154 mg,1.1 mmol) tetrahydrofuran (2.0 mL), N,N-dimethylformamide (1 drop),thionyl chloride (0.08 mL, 1.1 mmol) and N,N-dimethylacetamide (6.0 mL),and by a reaction in the same manner as in Example 203, the titlecompound (208 mg, 47%) was obtained as pale-yellow crystals.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.75-0.85 (4H, m), 1.85-2.00 (1H, m), 2.20(3H, s), 2.28 (3H, s), 3.88 (3H, s), 6.95-7.05 (1H, m), 7.02 (1H, d,J=9.6 Hz), 7.30 (1H, d, J=8.7 Hz), 7.63 (1H, s), 7.65-7.70 (1H, m), 7.93(1H, s), 8.02 (1H, d, J=9.6 Hz), 9.28 (1H, s), 11.06 (1H, s).

Example 210 Production ofN-{2-fluoro-5-[(2-{[(methoxyamino)carbonyl]amino}imidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide

UsingN-{5-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]-2-fluorophenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamidehydrochloride (200 mg, 0.48 mmol), 1,1′-carbonylimidazole (233 mg, 1.44mmol), O-methylhydroxyammonium chloride (120 mg, 1.44 mmol),triethylamine (0.27 mL, 1.92 mmol) and N,N-dimethylformamide (6.0 mL),and by a reaction in the same manner as in Example 200, the titlecompound (117 mg, 54%) was obtained as pale-yellow crystals.

¹H-NMR (DMSO-d₆, 300 MHz) δ 2.19 (3H, s), 3.60 (3H, s), 3.97 (3H, s),6.84 (1H, s), 7.05 (1H, d, J=9.6 Hz), 7.15-7.25 (1H, m), 7.39 (1H, t,J=9.0 Hz), 7.50-7.55 (1H, m), 7.83 (1H, s), 8.01 (1H, d, J=9.6 Hz), 9.46(1H, s), 9.67 (1H, s), 10.09 (1H, s).

Example 211 Production ofN-(2-fluoro-5-{[2-(glycoloylamino)imidazo[1,2-b]pyridazin-6-yl]oxy}phenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide

ToN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide(507 mg, 1.13 mmol) was added 10% hydrogen chloride methanol solution(30 mL), and the mixture was stirred at 50° C. for 23 hr. The solventwas evaporated under reduced pressure. To the residue were addedacetoxyacetic acid (242 mg, 2.05 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (336 mg,1.75 mmol), 1-hydroxybenzotriazole (167 mg, 1.24 mmol),N-ethyldiisopropylamine (0.60 mL, 3.51 mmol) and N,N-dimethylformamide(10 mL), and the mixture was stirred at room temperature for 62 hr.Methanol (10 mL), water (10 mL) and saturated aqueous sodium carbonatesolution (2 mL) were added to the mixture, and the mixture was stirredat room temperature for 2 hr and concentrated under reduced pressure. Asaturated aqueous sodium hydrogencarbonate solution was added to theresidue, and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated brine, dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. The residue wasseparated and purified by NH silica gel column chromatography (ethylacetate/hexane=0/100→100/0-methanol/ethyl acetate=2/98) and crystallizedfrom ethanol to give the title compound (94 mg, 19%) as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 2.19 (3H, s), 3.98 (3H, s), 4.05 (2H, d,J=6.0 Hz), 5.51 (1H, t, J=6.0 Hz), 6.85 (1H, s), 7.11 (1H, d, J=9.8 Hz),7.18-7.27 (1H, m), 7.41 (1H, m), 7.55 (1H, dd, J=6.4, 3.0 Hz), 8.01 (1H,s), 8.07 (1H, d, J=9.0 Hz), 10.11 (1H, s), 10.23 (1H, s).

Example 212 Production ofN-{2-fluoro-5-[(2-{[(4-methylpiperazin-1-yl)acetyl]amino}imidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamidedihydrochloride

ToN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide(1.05 mg, 2.33 mmol) was added 10% hydrogen chloride methanol solution(120 mL), and the mixture was stirred at 50° C. for 44 hr. The solventwas evaporated under reduced pressure. To a half of the residue wereadded (4-methylpiperazin-1-yl)acetic acid (205 mg, 1.30 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (284 mg,1.48 mmol), 1-hydroxybenzotriazole (167 mg, 1.24 mmol),N-ethyldiisopropylamine (0.60 mL, 3.51 mmol) and N,N-dimethylformamide(10 mL), and the mixture was stirred at room temperature for 11 hr. Asaturated aqueous sodium hydrogencarbonate solution was added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (ethylacetate/hexane=0/100→70/30) and the objective fraction was concentratedunder reduced pressure. The residue was dissolved in methanol andtreated with a 4N hydrogen chloride ethyl acetate solution to give thetitle compound (43 mg, 6%) as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 2.19 (3H, s), 2.78 (3H, s), 3.21 (1H, brs),3.34 (1H, brs), 3.67 (1H, br), 3.98 (3H, s), 6.87 (1H, s), 7.13 (1H, d,J=9.5 Hz), 7.18-7.27 (1H, m), 7.41 (1H, t, J=9.7 Hz), 7.51-7.60 (1H, m),8.02 (1H, s), 8.09 (1H, d, J=9.5 Hz), 10.13 (1H, s), 11.03 (1H, s).

Example 213 Production ofN-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-1-methyl-1H-pyrrole-2-carboxamide

Using 1-methyl-1H-pyrrole-2-carboxylic acid (97 mg, 0.78 mmol),tetrahydrofuran (4.0 mL), N,N-dimethylformamide (30 μL, 0.39 mmol),oxalyl chloride (135 μL, 1.55 mmol),N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropylcarboxamide(200 mg, 0.65 mmol) and N,N-dimethylacetamide (4.0 mL), and in the samemanner as in Example 119, the title compound (133 mg, 49%) was obtainedas a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.78-0.82 (4H, m), 1.88-1.96 (1H, m), 3.85(3H, s), 6.09 (1H, dd, J=3.9, 2.7 Hz), 6.91-6.95 (1H, m), 7.01-7.07 (3H,m), 7.35-7.41 (1H, m), 7.58-7.62 (1H, m), 7.66-7.68 (1H, m), 7.98 (1H,s), 8.05 (1H, d, J=9.6 Hz), 9.87 (1H, s), 11.09 (1H, s).

Example 214 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]cyclopentanecarboxamide

UsingN-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(200 mg, 0.62 mmol), N,N-dimethylacetamide (3.0 mL) andcyclopentanecarbonyl chloride (90 μL, 0.74 mmol), and in the same manneras in Example 120, the title compound (119 mg, 46%) was obtained as awhite powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.75-0.83 (4H, m), 1.48-1.96 (9H, m), 2.22(3H, s), 2.82-2.93 (1H, m), 6.97 (1H, dd, J=8.4, 2.6 Hz), 7.01 (1H, d,J=9.6 Hz), 7.26 (1H, d, J=8.4 Hz), 7.37 (1H, d, J=2.6 Hz), 7.93 (1H, s),8.01 (1H, d, J=9.6 Hz), 9.24 (1H, s), 11.07 (1H, s).

Example 215 Production ofN-[6-(3-{[(ethylamino)carbonyl]amino}-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide

To a solution ofN-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(200 mg, 0.62 mmol) in pyridine (4.0 mL) was added ethyl isocyanate (490μL, 6.19 mmol), and the mixture was stirred at room temperature for 16hr. The solvent was evaporated under reduced pressure and water wasadded to the residue. The mixture was extracted with ethylacetate/tetrahydrofuran, washed with saturated brine, dried overanhydrous sodium sulfate, and filtrated. The solvent was evaporatedunder reduced pressure, and the residue was washed with ethylacetate/ethanol and filtrated to give the title compound (142 mg, 58%)as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.76-0.83 (4H, m), 1.04 (3H, t, J=7.1 Hz),1.86-1.95 (1H, m), 2.19 (3H, s), 3.02-3.14 (2H, m), 6.64-6.75 (2H, m),6.98 (1H, d, J=9.6 Hz), 7.16 (1H, d, J=8.1 Hz), 7.71 (1H, s), 7.86 (1H,d, J=2.7 Hz), 7.93 (1H, s), 8.00 (1H, d, J=9.6 Hz), 11.07 (1H, s).

Example 216 Production ofN-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]acetamide

To a solution of 3-amino-4-methylphenol (1.22 g, 9.93 mmol) inN,N-dimethylformamide (25.0 mL) was added potassium tert-butoxide (1.16g, 10.3 mmol), and the mixture was stirred at room temperature for 2 hr.To the reaction mixture were addedN-(6-iodoimidazo[1,2-b]pyridazin-2-yl)acetamide (2.5 g, 8.28 mmol) andpotassium carbonate (0.57 g, 4.14 mmol), and the mixture was stirred at140° C. for 16 hr. Saturated brine was added to the reaction mixture,and the mixture was extracted with ethyl acetate/tetrahydrofuran, washedwith saturated brine, dried over anhydrous sodium sulfate, andfiltrated. The solvent was evaporated under reduced pressure, and theresidue was purified by silica gel column chromatography (ethyl acetatealone) and the obtained residue was washed with hexane/ethyl acetate,and filtrated to give the title compound (1.04 g, 42%) as a brownpowder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 2.05 (3H, s), 2.07 (3H, s), 5.06 (2H, s),6.28 (1H, d, J=8.1, 2.4 Hz), 6.42 (1H, d, J=2.4 Hz), 6.94 (1H, d, J=9.6Hz), 6.95 (1H, d, J=8.1 Hz), 7.97 (1H, d, J=8.1 Hz), 7.98 (1H, s), 10.78(1H, s).

Example 217 Production ofN-(6-phenoxyimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide

Using phenol (69 mg, 0.73 mmol), N,N-dimethylformamide (25.0 mL),potassium tert-butoxide (1.16 g, 10.3 mmol),N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (200 mg,0.61 mmol) and potassium carbonate (42 mg, 0.31 mmol), and in the samemanner as in Example 216, the title compound (98 mg, 54%) was obtainedas a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.76-0.83 (4H, m), 1.86-1.96 (1H, m), 7.03(1H, d, J=9.6 Hz), 7.23-7.29 (3H, m), 7.42-7.49 (2H, m), 7.92 (1H, s),8.02 (1H, d, J=9.6 Hz), 11.06 (1H, s).

Example 218 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]-1-methyl-1H-pyrrole-2-carboxamide

Using 1-methyl-1H-pyrrole-2-carboxylic acid (93 mg, 0.74 mmol),tetrahydrofuran (4.0 mL), N,N-dimethylformamide (30 μL, 0.39 mmol),oxalyl chloride (135 μL, 1.48 mmol),N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(200 mg, 0.62 mmol) and N,N-dimethylacetamide (4.0 mL), and in the samemanner as in Example 119, the title compound (15 mg, 6%) was obtained asa white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.76-0.83 (4H, m), 1.87-1.95 (1H, m), 2.25(3H, s), 3.84 (3H, s), 6.06-6.09 (1H, m), 6.96-7.03 (3H, m), 7.03 (1H,d, J=9.6 Hz), 7.26-7.32 (2H, m), 7.92 (1H, s), 8.02 (1H, d, J=9.6 Hz),9.35 (1H, s), 11.07 (1H, s).

Example 219 Production ofN-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-1-methyl-L-prolinamide

To a solution ofN-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropylcarboxamide(200 mg, 0.65 mmol) in N,N-dimethylformamide (4.0 mL) were added1-methyl-L-proline (167 mg, 1.29 mmol),O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(736 mg, 1.94 mmol), hydroxybenzotriazole (262 mg, 1.94 mmol) andN,N-diisopropylethylamine (338 μL, 1.94 mmol), and the mixture wasstirred at room temperature for 3 hr. Saturated aqueous sodiumhydrogencarbonate solution was added to the reaction mixture, and themixture was extracted with ethyl acetate, washed with saturated brine,dried over anhydrous sodium sulfate, and filtrated. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography (ethyl acetate/ethanol=8/1), and theobtained residue was recrystallized from ethyl acetate to give the titlecompound (86 mg, 32%) as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.76-0.83 (4H, m), 1.68-1.84 (3H, m),1.87-1.95 (1H, m), 2.06-2.18 (1H, m), 2.25-2.36 (1H, m), 2.32 (3H, s),2.85-2.92 (1H, m), 3.05-3.13 (1H, m), 6.91-6.95 (1H, m), 7.03 (1H, d,J=9.8 Hz), 7.32-7.39 (1H, m), 7.54-7.58 (1H, m), 7.65-7.68 (1H, m), 7.95(1H, s), 8.03 (1H, d, J=9.8 Hz), 9.81 (1H, s), 11.08 (1H, s).

Example 220 Production ofN-(5-{[2-(acetylamino)imidazo[1,2-b]pyridazin-6-yl]oxy}-2-methylphenyl)-1-methyl-1H-imidazole-2-carboxamide

To a solution ofN-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]acetamide(150 mg, 0.50 mmol) in N,N-dimethylformamide (3.0 mL) were added1-methyl-1H-imidazole-2-carboxylic acid (127 mg, 1.01 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (290 mg,1.51 mmol) and 1-hydroxybenzotriazole (205 mg, 1.51 mmol), and themixture was stirred at room temperature for 16 hr. Saturated aqueoussodium hydrogencarbonate solution was added to the reaction mixture, andthe mixture was extracted with ethyl acetate/tetrahydrofuran, washedwith saturated brine, dried over anhydrous sodium sulfate, andfiltrated. The solvent was evaporated under reduced pressure, and theobtained residue was recrystallized from ethyl acetate/ethanol to givethe title compound (115 mg, 56%) as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 2.05 (3H, s), 2.30 (3H, s), 3.97 (3H, s),6.96-7.09 (3H, m), 7.33 (1H, d, J=8.4 Hz), 7.45 (1H, s), 7.68 (1H, d,J=2.4 Hz), 7.95 (1H, s), 8.02 (1H, d, J=9.9 Hz), 9.77 (1H, s), 10.78(1H, s).

Example 221 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]-1-methyl-1H-imidazole-2-carboxamide

To a solution ofN-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(150 mg, 0.46 mmol) in N,N-dimethylformamide (3.0 mL) were added1-methyl-1H-imidazole-2-carboxylic acid (117 mg, 0.93 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (267 mg,1.39 mmol) and 1-hydroxybenzotriazole (188 mg, 1.39 mmol), and themixture was stirred at room temperature for 16 hr. Saturated aqueoussodium hydrogencarbonate solution was added to the reaction mixture, andthe mixture was extracted with ethyl acetate/tetrahydrofuran, washedwith saturated brine, dried over anhydrous sodium sulfate, andfiltrated. The solvent was evaporated under reduced pressure, and theobtained residue was washed with ethyl acetate/hexane to give the titlecompound (66 mg, 32%) as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.76-0.83 (4H, m), 1.85-1.96 (1H, m), 2.30(3H, s), 3.96 (3H, s), 6.98-7.03 (2H, m), 7.07 (1H, d, J=9.5 Hz), 7.32(1H, d, J=8.4 Hz), 7.42 (1H, s), 7.68 (1H, d, J=2.7 Hz), 7.93 (1H, s),8.02 (1H, d, J=9.5 Hz), 9.76 (1H, s), 11.06 (1H, s).

Example 222 Production ofN-(6-{4-methyl-3-[(3-methylbut-2-enoyl)amino]phenoxy}imidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide

UsingN-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(200 mg, 0.62 mmol), N,N-dimethylacetamide (2.0 mL) and3,3-dimethylacryloyl chloride (83 μL, 0.74 mmol), and in the same manneras in Example 120, the title compound (142 mg, 57%) was obtained as awhite powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.75-0.84 (4H, m), 1.86 (3H, s), 1.87-1.93(1H, m), 2.11 (3H, s), 2.22 (3H, s), 5.99 (1H, s), 6.94 (1H, dd, J=8.3,2.6 Hz), 7.01 (1H, d, J=9.6 Hz), 7.25 (1H, d, J=8.3 Hz), 7.49 (1H, d,J=2.6 Hz), 7.92 (1H, s), 8.02 (1H, d, J=9.6 Hz), 9.14 (1H, s), 11.05(1H, s).

Example 223 Production of3-tert-butyl-N-[5-({2[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]-1-methyl-1H-pyrazole-5-carboxamide

Using 3-tert-butyl-1-methyl-1H-pyrazole-5-carboxylic acid (61 mg, 0.33mmol), tetrahydrofuran (1.8 mL), N,N-dimethylformamide (30 μL, 0.39mmol), oxalyl chloride (44 μL, mmol),N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(90 mg, 0.28 mmol) and N,N-dimethylacetamide (1.8 mL), and in the samemanner as in Example 119, the title compound (55 mg, 41%) was obtainedas a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.75-0.83 (4H, m), 1.27 (9H, s), 1.86-1.94(1H, m), 2.25 (3H, s), 3.99 (3H, s), 6.92 (1H, s), 7.04 (1H, d, J=9.5Hz), 7.09 (1H, dd, J=8.4, 2.4 Hz), 7.25 (1H, d, J=2.4 Hz), 7.34 (1H, d,J=8.4 Hz), 7.94 (1H, s), (1H, d, J=9.5 Hz), 9.84 (1H, s), 11.07 (1H, s).

Example 224 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]cyclopent-1-ene-1-carboxamide

UsingN-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(200 mg, 0.62 mmol), N,N-dimethylacetamide (4.0 mL),1-cyclopentenecarboxylic acid (139 mg, 1.24 mmol),O-(benzotriazol-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate(704 mg, 1.86 mmol), 1-hydroxybenzotriazole (251 mg, 1.86 mmol) andN,N-diisopropylethylamine (323 μL, 1.86 mmol), and in the same manner asin Example 219, the title compound (69 mg, 21%) was obtained as a whitepowder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.76-0.83 (4H, m), 1.84-1.95 (3H, m), 2.21(3H, s), 2.40-2.61 (4H, m), 6.67-6.70 (1H, m), 7.00-7.04 (2H, m),7.23-7.30 (2H, m), 7.91 (1H, s), 8.01 (1H, d, J=9.3 Hz), 9.18 (1H, s),11.06 (1H, s).

Example 225 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]-1,2,5-trimethyl-1H-pyrrole-3-carboxamide

To a solution of 1,2,5-trimethylpyrrole-3-carboxylic acid (142 mg, 0.93mmol) in tetrahydrofuran (4.0 mL) were added N,N-dimethylformamide (20μL, 0.26 mmol) and oxalyl chloride (108 μL, 1.24 mmol), and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasadded to a solution ofN-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(200 mg, 0.62 mmol) and triethylamine (259 μL, 1.86 mmol) inN,N-dimethylacetamide (4.0 mL), and the mixture was stirred at 50° C.for 16 hr. Water was added to the reaction mixture, and the mixture wasextracted with ethyl acetate, washed with saturated brine, dried overanhydrous sodium sulfate, and filtrated. The solvent was evaporatedunder reduced pressure, and the residue was purified by silica gelcolumn chromatography (hexane/ethyl acetate=1/3→ethyl acetate alone),washed with hexane/ethyl acetate and filtrated to give the titlecompound (68 mg, 24%) as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.75-0.83 (4H, m), 1.86-1.94 (1H, m), 2.17(3H, s), 2.23 (3H, s), 2.44 (3H, s), 3.37 (3H, s), 6.35 (1H, s), 6.96(1H, dd, J=8.1, 2.4 Hz), 7.01 (1H, d, J=9.6 Hz), 7.26 (1H, d, J=8.1 Hz),7.36 (1H, d, J=2.4 Hz), 7.92 (1H, s), 8.01 (1H, d, J=9.6 Hz), 8.73 (1H,s), 11.05 (1H, s).

Example 226 Production ofN-[6-(3-amino-4-methoxyphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide

Using 3-amino-4-methoxyphenol (408 mg, 2.93 mmol), N,N-dimethylformamide(16 mL), potassium tert-butoxide (343 mg, 3.05 mmol),N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)acetamide (800 mg, 2.44 mmol) andpotassium carbonate (169 mg, 1.22 mmol), and in the same manner as inExample 216, the title compound (1.04 g, 42%) was obtained as a brownpowder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.76-0.83 (4H, m), 1.86-1.94 (1H, m), 3.77(3H, s), 4.95 (2H, s), 6.33 (1H, dd, J=8.7, 2.9 Hz), 6.46 (1H, d, J=2.9Hz), 6.79 (1H, d, J=8.7 Hz), 6.91 (1H, d, J=9.6 Hz), 7.93 (1H, s), 7.96(1H, d, J=9.6 Hz), 11.04 (1H, s).

Example 227 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methoxyphenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide

UsingN-[6-(3-amino-4-methoxyphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(200 mg, 0.59 mmol), N,N-dimethylacetamide (4.0 mL) and1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (113 mg, 0.71 mmol), and inthe same manner as in Example 120, the title compound (146 mg, 54%) wasobtained as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.76-0.83 (4H, m), 1.87-1.96 (1H, m), 2.19(3H, s), 3.88 (3H, s), 3.97 (3H, s), 6.82 (1H, s), 7.03 (1H, d, J=9.6Hz), 7.07-7.19 (2H, m), 7.70 (1H, d, J=3.0 Hz), 7.92 (1H, s), 8.02 (1H,d, J=9.6 Hz), 9.35 (1H, s), 11.06 (1H, s).

Example 228 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-1-methyl-1H-imidazole-2-carboxamide

To a solution ofN-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(200 mg, 0.61 mmol) in N,N-dimethylformamide (4.0 mL) were added1-methyl-1H-imidazole-2-carboxylic acid (154 mg, 1.22 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (351 mg,1.83 mmol) and 1-hydroxybenzotriazole (248 mg, 1.83 mmol), and themixture was stirred at room temperature for 16 hr. Saturated aqueoussodium hydrogencarbonate solution was added to the reaction mixture, andthe mixture was extracted with ethyl acetate/tetrahydrofuran, washedwith saturated brine, dried over anhydrous sodium sulfate, andfiltrated. The solvent was evaporated under reduced pressure, and theobtained residue was purified by silica gel column chromatography (ethylacetate alone) to give the title compound (31 mg, 12%) as a whitepowder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.76-0.83 (4H, m), 1.86-1.96 (1H, m), 3.97(3H, s), 7.03-7.17 (3H, m), 7.37-7.48 (2H, m), 7.88 (1H, dd, J=6.5, 2.9Hz), 7.94 (1H, s), 8.04 (1H, d, J=9.9 Hz), 9.91 (1H, s), 11.07 (1H, s).

Example 229 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-1,5-dimethyl-1H-pyrazole-3-carboxamide

To a solution ofN-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(200 mg, 0.61 mmol) in N,N-dimethylformamide (4.0 mL) were added1,5-dimethyl-1H-pyrazole-3-carboxylic acid (171 mg, 1.22 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (351 mg,1.83 mmol), 1-hydroxybenzotriazole (248 mg, 1.83 mmol) and triethylamine(256 μL, 1.83 mmol), and the mixture was stirred at 60° C. for 36 hr.Water was added to the reaction mixture, and the mixture was extractedwith ethyl acetate/tetrahydrofuran, washed with saturated brine, driedover anhydrous sodium sulfate, and filtrated. The solvent was evaporatedunder reduced pressure, and the obtained residue was purified by silicagel column chromatography (ethyl acetate/hexane=3/1→ethyl acetate alone)to give the title compound (72 mg, 26%) as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.76-0.82 (4H, m), 1.87-1.96 (1H, m), 2.30(3H, s), 3.84 (3H, s), 6.57 (1H, s), 7.07 (1H, d, J=9.6 Hz), 7.07-7.14(1H, m), 7.35-7.43 (1H, m), 7.89 (1H, dd, J=6.3, 3.0 Hz), 7.95 (1H, s),8.04 (1H, d, J=9.6 Hz), 9.46 (1H, s), 11.08 (1H, s).

Example 230 Production ofN-{6-[3-({[(1,3-dimethyl-1H-pyrazol-5-yl)amino]carbonyl}amino)-4-methylphenoxy]imidazo[1,2-b]pyridazin-2-yl}cyclopropanecarboxamide

To a solution of 1,3-dimethyl-1H-pyrazol-5-amine (104 mg, 0.93 mmol) inN,N-dimethylformamide (4.0 mL) was added N,N-carbonyldiimidazole (150mg, 0.93 mmol), and the mixture was stirred at room temperature for 30min. To the reaction mixture was addedN-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(200 mg, 0.62 mmol), and the mixture was stirred at room temperature for16 hr. Water was added to the reaction mixture, and the mixture wasextracted with ethyl acetate/tetrahydrofuran, washed with saturatedbrine, dried over anhydrous sodium sulfate, and filtrated. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography (ethanol/ethyl acetate=1/20→1/10) togive the title compound (58 mg, 20%) as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.76-0.82 (4H, m), 1.87-1.95 (1H, m), 2.05(3H, s), 2.27 (3H, s), 3.59 (3H, s), 5.94 (1H, s), 6.83 (1H, dd, J=8.0,2.6 Hz), 7.00 (1H, d, J=9.5 Hz), 7.24 (1H, d, J=8.4 Hz), 7.80 (1H, d,J=2.6 Hz), 7.92 (1H, s), 8.00 (1H, d, J=9.5 Hz), 8.25 (1H, s), 8.99 (1H,s), 11.05 (1H, s).

Example 231 Production ofN-[6-(3-{[(2,4-dimethyl-1,3-thiazol-5-yl)sulfonyl]amino}-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide

To a solution ofN-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(200 mg, 0.62 mmol) in pyridine (4.0 mL) was added2,4-dimethyl-1,3-thiazole-5-sulfonyl chloride (157 mg, 0.74 mmol), andthe mixture was stirred at room temperature for 16 hr. Water was addedto the reaction mixture, and the mixture was extracted with ethylacetate, washed with saturated brine, dried over anhydrous sodiumsulfate, and filtrated. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography (ethyl acetate/hexane=3/1→ethyl acetate alone) and washedwith hexane/ethyl acetate to give the title compound (196 mg, 64%) as awhite powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.76-0.86 (4H, m), 1.88-1.95 (1H, m), 2.07(3H, s), 2.20 (3H, s), 2.55 (3H, s), 6.92 (1H, d, J=2.7 Hz), 7.01 (1H,d, J=9.8 Hz), 7.07-7.12 (1H, dd, J=8.4, 2.7 Hz), 7.27 (1H, d, J=8.4 Hz),7.93 (1H, s), 8.02 (1H, d, J=9.8 Hz), 10.10 (1H, s), 11.08 (1H, s).

Example 232 Production ofN-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]acetamide

To a solution of N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)acetamide (12 g,39.7 mmol) in N,N-dimethylformamide (120 mL) were added3-amino-4-fluorophenol (7.6 g, 59.6 mmol) and potassium carbonate (11.0g, 79.5 mmol), and the mixture was stirred at 140° C. for 12 hr. Aftercooling the mixture to room temperature, water was added to the reactionmixture, and the mixture was extracted with ethylacetate/tetrahydrofuran, washed with saturated brine, dried overanhydrous sodium sulfate, and filtrated. The solvent was evaporatedunder reduced pressure, and the residue was purified by silica gelcolumn chromatography (ethyl acetate/hexane=3/1→ethyl acetate alone) togive the title compound (9.5 g, 79%) as a brown powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 2.07 (3H, s), 5.36 (2H, s), 6.30-6.37 (1H,m), 6.58 (1H, dd, J=7.8, 2.7 Hz), 6.97 (1H, d, J=9.6 Hz), 6.98-7.06 (1H,m), 7.99 (1H, d, J=9.6 Hz), 8.00 (1H, s), 10.78 (1H, s).

Example 233 Production ofN-(5-{[2-(acetylamino)imidazo[1,2-b]pyridazin-6-yl]oxy}-2-fluorophenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide

To a solution ofN-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]acetamide(5.6 g, 18.6 mmol) in N,N-dimethylacetamide (44.8 mL) was added1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (3.25 g, 20.4 mmol). Afterstirring at room temperature for 2 hr, water was added to the reactionmixture, and the mixture was extracted with ethylacetate/tetrahydrofuran, washed with saturated brine, dried overanhydrous magnesium sulfate, and filtrated. The solvent was evaporatedunder reduced pressure, and the residue was washed with ethylacetate/ethanol to give the title compound (6.1 g, 78%) as a whitepowder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 2.06 (3H, s), 2.19 (3H, s), 3.97 (3H, s),6.85 (1H, s), 7.07 (1H, d, J=9.6 Hz), 7.17-7.25 (1H, m), 7.34-7.44 (1H,m), 7.50-7.58 (1H, m), 7.96 (1H, s), 8.04 (1H, d), 10.10 (1H, s), 10.79(1H, s).

Example 234 Production ofN-[6-(5-amino-2-chloro-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide

To a solution ofN-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (600 mg,1.83 mmol) in N,N-dimethylformamide (12 mL) were added3-amino-6-chloro-4-fluorophenol (443 mg, 2.74 mmol) and potassiumcarbonate (505 mg, 3.66 mmol). In the same manner as in Example 232, thetitle compound (372 mg, 56%) was obtained as a brown powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.76-0.83 (4H, m), 1.87-1.95 (1H, m), 5.56(2H, s), 6.74 (1H, d, J=8.4 Hz), 7.07 (1H, d, J=9.5 Hz), 7.34 (1H, d,J=10.5 Hz), 7.94 (1H, s), 8.04 (1H, d, J=9.5 Hz), 11.07 (1H, s).

Example 235 Production ofN-[4-chloro-5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide

UsingN-[6-(5-amino-2-chloro-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(200 mg, 0.55 mmol), N,N-dimethylacetamide (4.0 mL) and1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (105 mg, 0.66 mmol), and inthe same manner as in Example 120, the title compound (108 mg, 40%) wasobtained as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.78-0.84 (4H, m), 1.85-1.96 (1H, m), 2.19(3H, s), 3.97 (3H, s), 6.84 (1H, s), 7.16 (1H, d, J=9.6 Hz), 7.74-7.81(2H, m), 7.90 (1H, s), 8.08 (1H, d, J=9.6 Hz), 10.19 (1H, s), 11.07 (1H,s).

Example 236 Production ofN-{5-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]-2-fluorophenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide.hydrochloride

To a suspension ofN-[4-chloro-5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide(2.0 g, 4.72 mmol) in methanol (20 mL) was added 4N hydrochloricacid/ethyl acetate (16 mL) solution. After stirring at room temperaturefor 4 hr, the mixture was stirred at 50° C. for 12 hr. The solvent wasevaporated under reduced pressure, and diisopropyl ether/ethanol (8 mL/2mL) was added to the residue. The mixture was stirred at roomtemperature for 2 hr. The precipitate was collected by filtration andwashed with diisopropyl ether to give the title compound (2.0 g, quant.)as a brown powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 2.19 (3H, s), 3.98 (3H, s), 6.91 (1H, s),7.18-7.26 (1H, m), 7.37 (1H, d, J=9.6 Hz), 7.39-7.48 (2H, m), 7.54-7.60(1H, m), 8.20 (1H, d, J=9.6 Hz), 10.24 (1H, s).

Example 237 Production ofN-(2-fluoro-5-{[2-(propionylamino)imidazo[1,2-b]pyridazin-6-yl]oxy}phenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide

To a solution ofN-{5-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]-2-fluorophenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide.hydrochloride(200 mg, 0.48 mmol) in N,N-dimethylacetamide (2.0 mL) was addedpropionyl chloride (49.9 μL, 0.57 mmol), and the mixture was stirred atroom temperature for 2 hr. Water was added to the reaction mixture, andthe mixture was extracted with ethyl acetate, washed with saturatedbrine, dried over anhydrous sodium sulfate, and filtrated. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography (ethyl acetate/hexane=3/1→ethyl acetatealone) and washed with ethyl acetate to give the title compound (78 mg,37%) as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.06 (3H, t, J=7.5 Hz), 2.19 (3H, s), 2.37(2H, q, J=7.5 Hz), 3.98 (3H, s), 6.85 (1H, s), 7.07 (1H, d, J=9.6 Hz),7.18-7.24 (1H, m), 7.37-7.44 (1H, m), 7.55 (1H, dd, J=6.3, 3.3 Hz), 7.98(1H, s), 8.08 (1H, d, J=9.6 Hz), 10.11 (1H, s), 10.74 (1H, s).

Example 238 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-1-methyl-1H-pyrazole-3-carboxamide

To a solution of 1-methyl-1H-pyrazole-3-carboxylic acid (115 mg, 0.92mmol) in tetrahydrofuran (4.0 mL) were added N,N-dimethylformamide (20μL, 0.26 mmol) and oxalyl chloride (80 μL, 0.92 mmol), and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasadded to a solution ofN-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(200 mg, 0.62 mmol) in N,N-dimethylacetamide (4.0 mL), and the mixturewas stirred at room temperature for 2 hr. Saturated aqueous sodiumhydrogencarbonate solution was added to the reaction mixture, and themixture was extracted with ethyl acetate/tetrahydrofuran, washed withsaturated brine, dried over anhydrous sodium sulfate, and filtrated. Thesolvent was evaporated under reduced pressure and ethanol (10 mL) wasadded to the residue. The mixture was stirred with heating at 75° C. andcooled to room temperature, and the precipitate was collected byfiltration to give the title compound (144 mg, 54%) as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.77-0.83 (4H, m), 1.87-1.97 (1H, m), 3.97(3H, s), 6.77 (1H, d, J=2.4 Hz), 7.06-7.16 (2H, m), 7.36-7.43 (1H, m),7.82-7.89 (2H, m), 7.95 (1H, s), 8.05 (1H, d, J=9.6 Hz), 9.59 (1H, s),11.08 (1H, s).

Example 239 Production ofN-{2-fluoro-5-[(2-{[(2,2,3,3-tetramethylcyclopropyl)carbonyl]amino}imidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide

To a solution of 2,2,3,3-tetramethylcyclopropanecarboxylic acid (102 mg,0.72 mmol) in tetrahydrofuran (4.0 mL) were added N,N-dimethylformamide(20 μL, 0.26 mmol) and oxalyl chloride (63 mL, 0.72 mmol), and themixture was stirred at room temperature for 30 min. The reaction mixturewas added to a solution ofN-{5-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]-2-fluorophenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide.hydrochloride(200 mg, 0.48 mmol) in N,N-dimethylacetamide (4.0 mL), and the mixturewas stirred at room temperature for 3 hr. Saturated aqueous sodiumhydrogencarbonate solution was added to the reaction mixture, and themixture was extracted with ethyl acetate/tetrahydrofuran, washed withsaturated brine, dried over anhydrous sodium sulfate, and filtrated. Thesolvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography (ethyl acetate/hexane=3/1)and precipitated from hexane/ethyl acetate to give the title compound(46 mg, 19%) as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.16 (6H, s), 1.22 (6H, s), 1.47 (1H, s),2.19 (3H, s), 3.97 (3H, s), 6.83 (1H, s), 7.04 (1H, d, J=9.5 Hz),7.17-7.22 (1H, m), 7.34-7.42 (1H, m), 7.51-7.55 (1H, m), 7.95 (1H, s),8.01 (1H, d, J=9.5 Hz), 10.09 (1H, s), 11.70 (1H, s).

Example 240 Production ofN-[5-({2-[(cyclopropylsulfonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide

To a solution ofN-{5-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]-2-fluorophenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide.hydrochloride(400 mg, 0.97 mmol) in 1-methyl-2-pyrrolidone (4.0 mL) were addedtriethylamine (404 μL, 2.90 mmol) and cyclopropanesulfonyl chloride (204mg, 1.45 mmol), and the mixture was stirred at 70° C. for 16 hr. Aftercooling the mixture to room temperature, water was added to the reactionmixture, and the mixture was extracted with ethylacetate/tetrahydrofuran, washed with saturated brine, dried overanhydrous sodium sulfate, and filtrated. The solvent was evaporatedunder reduced pressure, and the residue was purified by silica gelcolumn chromatography (ethyl acetate alone) and precipitated fromhexane/ethyl acetate to give the title compound (74 mg, 16%) as a whitepowder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.92-1.03 (4H, m), 2.19 (3H, s), 2.75-2.86(1H, m), 3.97 (3H, s), 6.84 (1H, s), 7.10 (1H, d, J=9.6 Hz), 7.18-7.25(1H, m), 7.36-7.43 (1H, m), 7.52-7.56 (1H, m), 7.63 (1H, s), 8.06 (1H,d, J=9.6 Hz), 10.09 (1H, s), 10.30 (1H, s).

Example 241 Production ofN-{6-[3-(but-2-ynoylamino)-4-methylphenoxy]imidazo[1,2-b]pyridazin-2-yl}cyclopropanecarboxamide

Using 2-butynoic acid (78 mg, 0.93 mmol), tetrahydrofuran (4.0 mL),N,N-dimethylformamide (20 μL, 0.26 mmol), oxalyl chloride (81 μL, 0.93mmol),N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(200 mg, 0.62 mmol) and N,N-dimethylacetamide (4.0 mL), and in the samemanner as in Example 238, the title compound (47 mg, 20%) was obtainedas a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.76-0.86 (4H, m), 1.85-1.95 (1H, m), 2.03(3H, s), 2.21 (3H, s), 6.96-7.04 (2H, m), 7.25-7.29 (2H, m), 7.92 (1H,s), 8.10 (1H, d, J=9.3 Hz), 10.05 (1H, s), 11.05 (1H, s).

Example 242 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-1-ethyl-1H-pyrazole-3-carboxamide

Using 1-ethyl-1H-pyrazole-3-carboxylic acid (128 mg, 0.92 mmol),tetrahydrofuran (2.0 mL), N,N-dimethylformamide (20 μL, 0.26 mmol),oxalyl chloride (80 μL, 0.92 mmol),N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(200 mg, 0.61 mmol) and N,N-dimethylacetamide (4.0 mL), and in the samemanner as in Example 238, the title compound (111 mg, 40%) was obtainedas a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.76-0.85 (4H, m), 1.44 (3H, t, J=7.2 Hz),1.87-1.97 (1H, m), 4.26 (2H, q, J=7.2 Hz), 6.77 (1H, d, J=2.1 Hz), 7.07(1H, d, J=9.6 Hz), 7.09-7.16 (1H, m), 7.39 (1H, dd, J=11.4, 8.7 Hz),7.84 (1H, dd, J=6.5, 2.9 Hz), 7.91-7.96 (2H, m), 8.04 (1H, d, J=9.6 Hz),9.57 (1H, s), 11.07 (1H, s).

Example 243 Production ofN-{2-fluoro-5-[(2-{[(2-methylcyclopropyl)carbonyl]amino}imidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide

Using 2-methylcyclopropanecarboxylic acid (72 mg, 0.72 mmol),tetrahydrofuran (2.0 mL), N,N-dimethylformamide (20 μL, 0.26 mmol),oxalyl chloride (63 μL, 0.72 mmol),N-{5-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]-2-fluorophenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide.hydrochloride(200 mg, 0.48 mmol) and N,N-dimethylacetamide (4.0 mL), and in the samemanner as in Example 239, the title compound (55 mg, 25%) was obtainedas a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.61-0.72 (1H, m), 0.95-1.05 (1H, m),1.06-1.09 (3H, m), 1.18-1.27 (1H, m), 1.64-1.73 (1H, m), 2.19 (3H, s),3.98 (3H, s), 6.84 (1H, s), 7.07 (1H, d, J=9.6 Hz), 7.09-7.24 (1H, m),7.36-7.43 (1H, m), 7.52-7.56 (1H, m), 7.93 (1H, s), 8.04 (1H, d, J=9.6Hz), 10.10 (1H, s), 10.99 (1H, s).

Example 244 Production ofN-{5-[(2-{[(2,2-dimethylcyclopropyl)carbonyl]amino}imidazo[1,2-b]pyridazin-6-yl)oxy]-2-fluorophenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide

Using 2,2-dimethylcyclopropanecarboxylic acid (82 mg, 0.72 mmol),tetrahydrofuran (3.0 mL), N,N-dimethylformamide (20 μL, 0.26 mmol),oxalyl chloride (63 μL, 0.72 mmol),N-{5-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]-2-fluorophenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide.hydrochloride(200 mg, 0.48 mmol) and N,N-dimethylacetamide (4.0 mL), and in the samemanner as in Example 239, the title compound (37 mg, 16%) was obtainedas a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.76-1.27 (2H, m), 1.12 (3H, s), 1.14 (3H,s), 1.75-1.84 (1H, m), 2.19 (3H, s), 3.97 (3H, s), 6.83 (1H, s), 7.05(1H, d, J=8.7 Hz), 7.16-7.24 (1H, m), 7.35-7.42 (1H, m), 7.50-7.55 (1H,m), 7.95 (1H, s), 8.03 (1H, d, J=8.7 Hz), 10.09 (1H, s), 10.90 (1H, s).

Example 245 Production ofN-(5-{[2-(acetylamino)imidazo[1,2-b]pyridazin-6-yl]oxy}-2-fluorophenyl)-3-ethyl-1-methyl-1H-pyrazole-5-carboxamide

Using 3-ethyl-1-methyl-1H-pyrazole-5-carboxylic acid (215 mg, 1.39mmol), tetrahydrofuran (4.5 mL), N,N-dimethylformamide (30 μL, 0.39mmol), oxalyl chloride (122 μL, 1.39 mmol),N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]acetamide(300 mg, 1.00 mmol) and N,N-dimethylacetamide (6.0 mL), and in the samemanner as in Example 238, the title compound (219 mg, 50%) was obtainedas a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.19 (3H, t, J=7.5 Hz), 2.06 (3H, s), 2.55(2H, q, J=7.5 Hz), 3.99 (3H, s), 6.89 (1H, s), 7.07 (1H, d, J=9.6 Hz),7.18-7.25 (1H, m), 7.36-7.43 (1H, m), 7.52-7.56 (1H, m), 7.95 (1H, s),8.03 (1H, d, J=9.6 Hz), 10.10 (1H, s), 10.78 (1H, s).

Example 246 Production ofN-[2-chloro-5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-3-methoxy-1-methyl-1H-pyrazole-5-carboxamide

Using 3-methoxy-1-methyl-1H-pyrazole-5-carboxylic acid (191 mg, 1.22mmol), tetrahydrofuran (4.5 mL), N,N-dimethylformamide (30 μL, 0.39mmol), oxalyl chloride (107 μL, 1.22 mmol),N-[6-(3-amino-4-chlorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(300 mg, 0.87 mmol) and N,N-dimethylacetamide (6.0 mL), and in the samemanner as in Example 238, the title compound (259 mg, 62%) was obtainedas a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.76-0.87 (4H, m), 1.86-1.99 (1H, m), 3.79(3H, s), 3.91 (3H, s), 6.47 (1H, s), 7.09 (1H, d, J=9.9 Hz), 7.23-7.28(1H, m), 7.49-7.53 (1H, m), 7.62 (1H, d, J=8.7 Hz), 7.94 (1H, s), 8.05(1H, d, J=9.9 Hz), 10.05 (1H, s), 11.07 (1H, s).

Example 247 Production ofN-[2-chloro-5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-3-ethyl-1-methyl-1H-pyrazole-5-carboxamide

Using 3-ethyl-1-methyl-1H-pyrazole-5-carboxylic acid (188 mg, 1.22mmol), tetrahydrofuran (4.5 mL), N,N-dimethylformamide (30 μL, 0.39mmol), oxalyl chloride (107 μL, 1.22 mmol),N-[6-(3-amino-4-chlorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(300 mg, 0.87 mmol) and N,N-dimethylacetamide (6.0 mL), and in the samemanner as in Example 238, the title compound (268 mg, 64%) was obtainedas a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.76-0.86 (4H, m), 1.19 (3H, t, J=7.7 Hz),1.84-1.97 (1H, m), 2.55 (2H, q, J=7.7 Hz), 3.99 (3H, s), 6.88 (1H, s),7.09 (1H, d, J=9.6 Hz), 7.25 (1H, dd, J=8.7, 2.9 Hz), 7.53 (1H, d, J=2.9Hz), 7.62 (1H, d, J=8.7 Hz), 7.95 (1H, s), 8.05 (1H, d, J=9.6 Hz), 10.00(1H, s), 11.07 (1H, s).

Example 248 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-2,5-dimethyl-1,3-oxazole-4-carboxamide

To a solution ofN-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(200 mg, 0.61 mmol) in N,N-dimethylacetamide (4.0 mL) was added2,5-dimethyl-1,3-oxazole-4-carbonyl chloride (127 mg, 0.79 mmol), andthe mixture was stirred at room temperature for 2 hr. Water was added tothe reaction mixture, and the mixture was extracted with ethyl acetate,washed with saturated brine, dried over anhydrous sodium sulfate, andfiltrated. The solvent was evaporated under reduced pressure, and theresidue was washed with ethanol to give the title compound (198 mg, 72%)as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.77-0.83 (4H, m), 1.86-1.97 (1H, m), 2.45(3H, s), 2.55 (3H, s), 7.06 (1H, d, J=9.6 Hz), 7.08-7.15 (1H, m),7.35-7.42 (1H, m), 7.87 (1H, dd, J=6.5, 2.9 Hz), 7.93 (1H, s), 8.03 (1H,d, J=9.6 Hz), 9.48 (1H, s), 11.06 (1H, s).

Example 249 Production of3-ethyl-N-{2-fluoro-5-[(2-{[(2-methylcyclopropyl)carbonyl]amino}imidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-1-methyl-1H-pyrazole-5-carboxamide

To a solution of 3-ethyl-1-methyl-1H-pyrazole-5-carboxylic acid (158 mg,1.03 mmol) in tetrahydrofuran (3.8 mL) were added N,N-dimethylformamide(20 μL, 0.26 mmol) and oxalyl chloride (90 μL, 1.03 mmol), and themixture was stirred at room temperature for 30 min. The reaction mixturewas added to a solution ofN-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]-2-methylcyclopropanecarboxamide(250 mg, 0.73 mmol) in N,N-dimethylacetamide (5.0 mL), and the mixturewas stirred at room temperature for 2 hr. Saturated aqueous sodiumhydrogencarbonate solution was added to the reaction mixture, and themixture was extracted with ethyl acetate/tetrahydrofuran, washed withsaturated brine, dried over anhydrous sodium sulfate, and filtrated. Thesolvent was evaporated under reduced pressure, the residue was purifiedby silica gel column chromatography (ethyl acetate alone) andrecrystallized from hexane/ethyl acetate to give the title compound (201mg, 57%) as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.61-0.71 (1H, m), 0.95-1.04 (1H, m),1.06-1.10 (3H, m), 1.19 (3H, t, J=7.7 Hz), 1.17-1.29 (1H, m), 1.61-1.72(1H, m), 2.57 (2H, q, J=7.7 Hz), 3.98 (3H, s), 6.89 (1H, s), 7.06 (1H,d, J=9.3 Hz), 7.18-7.22 (1H, m), 7.35-7.42 (1H, m), 7.50-7.53 (1H, m),7.92 (1H, s), 8.03 (1H, d, J=9.3 Hz), 10.10 (1H, s), 10.98 (1H, s).

Example 250 Production of3-methoxy-1-methyl-N-{2-methyl-5-[(2-{[(2-methylcyclopropyl)carbonyl]amino}imidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-1H-pyrazole-5-carboxamide

Using 3-methoxy-1-methyl-1H-pyrazole-5-carboxylic acid (194 mg, 1.24mmol), tetrahydrofuran (4.5 mL), N,N-dimethylformamide (30 μL, 0.39mmol), oxalyl chloride (109 μL, 1.22 mmol),N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]-2-methylcyclopropanecarboxamide(300 mg, 0.89 mmol) and N,N-dimethylacetamide (6.0 mL), and in the samemanner as in Example 249, the title compound (291 mg, 69%) was obtainedas a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.61-0.71 (1H, m), 0.95-1.04 (1H, m),1.06-1.09 (3H, m), 1.19-1.26 (1H, m), 1.62-1.72 (1H, m), 2.24 (3H, s),3.79 (3H, s), 3.91 (3H, s), 6.45 (1H, s), 7.03 (1H, d, J=9.3 Hz), 7.09(1H, dd, J=8.3, 2.6 Hz), 7.25 (1H, d, J=2.6 Hz), 7.34 (1H, d, J=8.3 Hz),7.91 (1H, s), 8.02 (1H, d, J=9.6 Hz), 9.84 (1H, s), 10.97 (1H, s).

Example 251 Production ofN-[2-chloro-5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-2,4-dimethyl-1,3-thiazole-5-carboxamide

Using 2,4-dimethyl-1,3-thiazole-5-carboxylic acid (192 mg, 1.22 mmol),tetrahydrofuran (4.5 mL), N,N-dimethylformamide (30 μL, 0.39 mmol),oxalyl chloride (107 μL, 1.22 mmol),N-[6-(3-amino-4-chlorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(300 mg, 0.87 mmol) and N,N-dimethylacetamide (6.0 mL), and in the samemanner as in Example 249, the title compound (206 mg, 49%) was obtainedas a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.77-0.82 (4H, m), 1.83-1.97 (1H, m), 2.59(3H, s), 2.64 (3H, s), 7.08 (1H, d, J=9.5 Hz), 7.20-7.24 (1H, m),7.59-7.63 (2H, m), 7.94 (1H, s), 8.05 (1H, d, J=9.5 Hz), 9.78 (1H, s),11.07 (1H, s).

Example 252 Production ofN-{2-chloro-5-[(2-{[(2-methylcyclopropyl)carbonyl]amino}imidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-ethyl-1-methyl-1H-pyrazole-5-carboxamide

Using 3-ethyl-1-methyl-1H-pyrazole-5-carboxylic acid (181 mg, 1.17mmol), tetrahydrofuran (4.5 mL), N,N-dimethylformamide (30 μL, 0.39mmol), oxalyl chloride (102 μL, 1.17 mmol),N-[6-(3-amino-4-chlorophenoxy)imidazo[1,2-b]pyridazin-2-yl]-2-methylcyclopropanecarboxamide(300 mg, 0.84 mmol) and N,N-dimethylacetamide (6.0 mL), and in the samemanner as in Example 249, the title compound (207 mg, 50%) was obtainedas a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.61-0.73 (1H, m), 0.97-1.04 (1H, m),1.05-1.09 (3H, m), 1.16-1.25 (1H, m), 1.19 (3H, t, J=7.5 Hz), 1.62-1.73(1H, m), 2.55 (2H, q, J=7.5 Hz), 3.99 (3H, s), 6.88 (1H, s), 7.08 (1H,d, J=9.5 Hz), 7.21-7.27 (1H, m), 7.53 (1H, d, J=3.0 Hz), 7.62 (1H, d,J=8.7 Hz), 7.94 (1H, s), 8.05 (1H, d, J=9.5 Hz), 10.00 (1H, s), 10.99(1H, s).

Example 253 Production ofN-[5-({2-[(cyclopropylsulfonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide

To a solution ofN-{5-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]-2-fluorophenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide.hydrochloride(400 mg, 0.97 mmol) in 1-methyl-2-pyrrolidone (4.0 mL) were addedtriethylamine (404 μL, 2.90 mmol) and cyclopropanesulfonyl chloride (204mg, 1.45 mmol), and the mixture was stirred at 70° C. for 16 hr. Aftercooling to room temperature, water was added to the reaction mixture,and the mixture was extracted with ethyl acetate/tetrahydrofuran, washedwith saturated brine, dried over anhydrous sodium sulfate, andfiltrated. The solvent was evaporated under reduced pressure, and theresidue was purified by silica gel column chromatography (ethyl acetatealone) and recrystallized from hexane/ethyl acetate to give the titlecompound (74 mg, 16%) as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.84-1.03 (4H, m), 2.19 (3H, s), 2.25 (3H,s), 2.72-2.86 (1H, m), 3.97 (3H, s), 6.80 (1H, s), 7.05-7.12 (2H, m),7.26-7.29 (1H, m), 7.34 (1H, d, J=8.4 Hz), 7.61 (1H, s), 8.04 (1H, d,J=9.6 Hz), 9.79 (1H, s), 10.29 (1H, s).

Example 254 Production ofN-[2-chloro-5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-1-ethyl-3-methyl-1H-pyrazole-4-carboxamide

Using 1-ethyl-3-methyl-1H-pyrazole-4-carboxylic acid (188 mg, 1.22mmol), tetrahydrofuran (4.5 mL), N,N-dimethylformamide (30 μL, 0.39mmol), oxalyl chloride (107 μL, 1.22 mmol),N-[6-(3-amino-4-chlorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(300 mg, 0.87 mmol) and N,N-dimethylacetamide (6.0 mL), and in the samemanner as in Example 249, the title compound (135 mg, 33%) was obtainedas a white powder. melting point 200° C.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.78-0.83 (4H, m), 1.38 (3H, t, J=7.2 Hz),1.78-1.96 (1H, m), 2.35 (3H, s), 4.09 (2H, q, J=7.2 Hz), 7.08 (1H, d,J=9.6 Hz), 7.15 (1H, dd, J=8.9, 3.0 Hz), 7.62 (1H, d, J=8.9 Hz), 7.65(1H, d, J=3.0 Hz), 7.95 (1H, s), 8.04 (1H, d, J=9.6 Hz), 8.36 (1H, s),9.30 (1H, s), 11.06 (1H, s).

Example 255 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-3-isopropyl-1-methyl-1H-pyrazole-5-carboxamide

To a solution of 3-isopropyl-1-methyl-1H-pyrazole-5-carboxylic acid (144mg, 0.86 mmol) in tetrahydrofuran (3.0 mL) were addedN,N-dimethylformamide (30 μL, 0.39 mmol) and oxalyl chloride (75 μL,0.86 mmol), and the mixture was stirred at room temperature for 30 min.The reaction mixture was added to a solution ofN-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(200 mg, 0.62 mmol) in N,N-dimethylacetamide (4.0 mL), and the mixturewas stirred at room temperature for 2 hr. Saturated aqueous sodiumhydrogencarbonate solution was added to the reaction mixture, and themixture was extracted with ethyl acetate/tetrahydrofuran, washed withsaturated brine, dried over anhydrous sodium sulfate, and filtrated. Thesolvent was evaporated under reduced pressure, and the residue waswashed with ethyl acetate to give the title compound (216 mg, 74%) as awhite powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.78-0.82 (4H, m), 1.21 (6H, d, J=6.6 Hz),1.85-1.96 (1H, m), 2.83-2.96 (1H, m), 3.98 (3H, s), 6.91 (1H, s), 7.06(1H, d, J=9.3 Hz), 7.17-7.22 (1H, m), 7.35-7.42 (1H, m), 7.50-7.54 (1H,m), 7.93 (1H, s), 8.03 (1H, d, J=9.3 Hz), 10.10 (1H, s), 11.06 (1H, s).

Example 256 Production ofN-{2-chloro-5-[(2-{[(2-methylcyclopropyl)carbonyl]amino}imidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-1-ethyl-3-methyl-1H-pyrazole-4-carboxamide

Using 1-ethyl-3-methyl-1H-pyrazole-4-carboxylic acid (181 mg, 1.17mmol), tetrahydrofuran (4.5 mL), N,N-dimethylformamide (30 μL, 0.39mmol), oxalyl chloride (102 μL, 1.17 mmol),N-[6-(3-amino-4-chlorophenoxy)imidazo[1,2-b]pyridazin-2-yl]-2-methylcyclopropanecarboxamide(300 mg, 0.84 mmol) and N,N-dimethylacetamide (6.0 mL), and in the samemanner as in Example 249, the title compound (118 mg, 28%) was obtainedas a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.61-0.69 (1H, m), 0.96-1.04 (1H, m),1.06-1.10 (3H, m), 1.18-1.29 (1H, m), 1.38 (3H, t, J=7.2 Hz), 1.62-1.71(1H, m), 2.35 (3H, s), 4.09 (2H, q, J=7.2 Hz), 7.07 (1H, d, J=9.6 Hz),7.15 (1H, dd, J=8.9, 3.2 Hz), 7.58 (1H, d, J=8.9 Hz), 7.64 (1H, d, J=3.2Hz), 7.93 (1H, s), 8.04 (1H, d, J=9.6 Hz), 8.36 (1H, s), 9.30 (1H, s),10.99 (1H, s).

Example 257 Production ofN-[6-(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)methyl]amino}-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide

A mixture ofN-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (210 mg,0.64 mmol),3-{[(1,3-dimethyl-1H-pyrazol-5-yl)methyl]amino}-4-methylphenol (220 mg,0.96 mmol), potassium carbonate (220 mg, 1.6 mmol) andN,N-dimethylformamide (1.5 mL) was stirred under microwave irradiationat 150° C. for 40 min. The solvent was evaporated under reducedpressure, ethyl acetate/tetrahydrofuran and water were added to theresidue, the aqueous layer was extracted with ethylacetate/tetrahydrofuran (×4). Combined organic layer was washed withsaturated brine, dried over anhydrous sodium sulfate, and filtrated. Thefiltrate was concentrated under reduced pressure, and the residue waspurified by silica gel column chromatography (methanol/ethylacetate=0/100→5/95) to give the title compound (200 mg, 72%) as a brownsolid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.74-0.84 (4H, m), 1.87-1.96 (1H, m), 2.00(3H, s), 2.11 (3H, s), 3.68 (3H, s), 4.26 (2H, d, J=5.7 Hz), 5.64 (1H,t, J=5.7 Hz), 5.80 (1H, s), 6.34 (1H, dd, J=7.9, 2.3 Hz), 6.40 (1H, d,J=2.3 Hz), 6.89 (1H, d, J=9.8 Hz), 7.01 (1H, d, J=8.5 Hz), 7.91-8.01(2H, m), 11.07 (1H, s).

Example 258 Production ofN-{6-[(2-methyl-1H-indol-6-yl)oxy]imidazo[1,2-b]pyridazin-2-yl}cyclopropanecarboxamide

A mixture ofN-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (360 mg,1.1 mmol), 2-methyl-1H-indole-6-ol (320 mg, 2.2 mmol), potassiumcarbonate (450 mg, 3.3 mmol) and N,N-dimethylformamide (4 mL) wasstirred at 120° C. for 24 hr. The solvent was evaporated under reducedpressure, ethyl acetate/tetrahydrofuran and water were added to theresidue, and the aqueous layer was extracted with ethylacetate/tetrahydrofuran (×4). Combined organic layer was washed withsaturated brine, dried over anhydrous sodium sulfate, and filtrated. Thefiltrate was concentrated under reduced pressure, and the residue waspurified by silica gel column chromatography (ethylacetate/hexane=20/80→90/10) to give the title compound (140 mg, 36%) asa brown solid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.72-0.86 (4H, m), 1.84-1.97 (1H, m), 2.39(3H, s), 6.15 (1H, s), 6.81 (1H, dd, J=8.5, 2.1 Hz), 6.96 (1H, d, J=9.8Hz), 7.13 (1H, d, J=2.1 Hz), 7.42 (1H, d, J=8.5 Hz), 7.90 (1H, s), 7.97(1H, d, J=9.8 Hz), 11.00 (1H, s), 11.04 (1H, s).

Example 259 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]-1-methyl-1H-pyrazole-5-carboxamide

To a solution of 1-methyl-1H-pyrazole-5-carboxylic acid (106 mg, 0.84mmol) in tetrahydrofuran (5 mL) were added N,N-dimethylformamide (1drop), oxalyl chloride (91 μL, 1.0 mmol), and the mixture was stirred atroom temperature for 30 min. The solvent was evaporated under reducedpressure, and the obtained 1-methyl-1H-pyrazole-5-carbonylchloride wasdissolved in N,N-dimethylacetamide (2 mL). This was added to a solutionofN-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(210 mg, 0.65 mmol) in N,N-dimethylacetamide (5 mL), and the mixture wasstirred at room temperature for 30 min. To the mixture were added ethylacetate/tetrahydrofuran and saturated aqueous sodium hydrogencarbonatesolution, and the aqueous layer was extracted with ethylacetate/tetrahydrofuran (×4). Combined organic layer was washed withwater and saturated brine, dried over anhydrous sodium sulfate, andfiltrated. The filtrate was concentrated under reduced pressure, and theresidue was purified by silica gel column chromatography (ethylacetate/hexane=30/70→90/10) to give the title compound (230 mg, 83%) asa white solid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.73-0.85 (4H, m), 1.87-1.97 (1H, m), 2.25(3H, s), 4.05 (3H, s), 7.00-7.07 (2H, m), 7.11 (1H, dd, J=8.3, 2.3 Hz),7.28 (1H, d, J=2.7 Hz), 7.36 (1H, d, J=8.3 Hz), 7.53 (1H, d, J=2.3 Hz),7.93 (1H, s), 8.03 (1H, d, J=9.5 Hz), 9.91 (1H, s), 11.07 (1H, s).

Example 260 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]-1-ethyl-3-methyl-1H-pyrazole-5-carboxamide

In the same manner as in Example 259 and using1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (130 mg, 0.84=mol),tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride(91 μL, 1.0 mmol),N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(210 mg, 0.65 mmol) and N,N-dimethylacetamide (7 mL) as startingmaterials, the title compound (220 mg, 75%) was obtained as a whitesolid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.71-0.83 (4H, m), 1.26 (3H, t, J=7.1 Hz),1.84-1.95 (1H, m), 2.18 (3H, s), 2.23 (3H, s), 4.39 (2H, q, J=7.1 Hz),6.78 (1H, s), 7.02 (1H, d, J=9.6 Hz), 7.08 (1H, dd, J=8.2, 2.7 Hz), 7.26(1H, d, J=2.7 Hz), 7.32 (1H, d, J=8.2 Hz), 7.91 (1H, s), 8.01 (1H, d,J=9.6 Hz), 9.79 (1H, s), 11.05 (1H, s).

Example 261 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]-2-methyl-1,3-thiazole-4-carboxamide

A mixture of 2-methyl-1,3-thiazole-4-carboxylic acid (120 mg, 0.84mmol),N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(210 mg, 0.65 mmol), 1-hydroxybenzotriazole (110 mg, 0.84 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (160 mg,0.84 mmol), triethylamine (85 mg, 0.84 mmol) and N,N-dimethylformamide(5 mL) was stirred at room temperature for 16 hr. The solvent wasevaporated under reduced pressure, ethyl acetate/tetrahydrofuran andwater were added to the residue, and the aqueous layer was extractedwith ethyl acetate/tetrahydrofuran (×4). Combined organic layer waswashed with saturated brine, dried over anhydrous sodium sulfate, andfiltrated. The filtrate was concentrated under reduced pressure, and theresidue was purified by silica gel column chromatography (ethylacetate/hexane=40/60→100/0) to give the title compound (180 mg, 62%) asa white solid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.71-0.82 (4H, m), 1.82-1.94 (1H, m), 2.27(3H, s), 2.72 (3H, s), 6.95-7.07 (2H, m), 7.32 (1H, d, J=8.8 Hz), 7.65(1H, d, J=2.7 Hz), 7.93 (1H, s), 8.01 (1H, d, J=9.6 Hz), 8.25 (1H, s),9.73 (1H, s), 11.06 (1H, s).

Example 262 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]-1-methyl-L-prolinamide

A mixture of 1-methyl-L-proline (170 mg, 1.3 mmol),N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(210 mg, 0.65 mmol), 1-hydroxybenzotriazole (175 mg, 1.3 mmol),O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(490 mg, 1.3 mmol), N,N-diisopropylethylamine (330 mg, 2.6 mmol) andN,N-dimethylformamide (15 mL) was stirred at room temperature for 18 hr,and then at 40° C. for 4 hr. The solvent was evaporated under reducedpressure, ethyl acetate/tetrahydrofuran and water were added to theresidue, the aqueous layer was extracted with ethylacetate/tetrahydrofuran (×4). Combined organic layer was washed withsaturated brine, dried over anhydrous sodium sulfate, and filtrated. Thefiltrate was concentrated under reduced pressure, and the residue waspurified by silica gel column chromatography (methanol/ethylacetate=0/100→10/90) to give the title compound (15 mg, 5%) as a whitesolid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.76-0.84 (4H, m), 1.69-1.86 (3H, m),1.87-1.99 (1H, m), 2.11-2.22 (1H, m), 2.23 (3H, s), 2.38 (1H, d, J=8.0Hz), 2.43 (3H, s), 2.95 (1H, dd, J=10.0, 4.7 Hz), 3.16 (1H, dd, J=7.4,4.7 Hz), 6.95 (1H, dd, J=8.3, 2.7 Hz), 7.02 (1H, d, J=9.5 Hz), 7.29 (1H,d, J=8.3 Hz), 7.77 (1H, d, J=2.7 Hz), 7.92 (1H, s), 8.02 (1H, d, J=9.5Hz), 9.61 (1H, s), 11.07 (1H, s).

Example 263 Production ofN-[6-(4-chloro-3-{[(1,3-dimethyl-1H-pyrazol-5-yl)methyl]amino}phenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide

In the same manner as in Example 257 and usingN-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (210 mg,0.65 mmol),4-chloro-3-{[(1,3-dimethyl-1H-pyrazol-5-yl)methyl]amino}phenol (240 mg,0.97 mmol), potassium carbonate (220 mg, 1.6 mmol) andN,N-dimethylformamide (1.5 mL) as starting materials, the title compound(180 mg, 61%) was obtained as a brown solid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.72-0.86 (4H, m), 1.86-1.91 (1H, m), 1.98(3H, s), 3.68 (3H, s), 4.35 (2H, d, J=6.1 Hz), 5.78 (1H, s), 6.11 (1H,t, J=6.1 Hz), 6.46 (1H, dd, J=8.7, 2.7 Hz), 6.61 (1H, d, J=2.7 Hz), 6.96(1H, d, J=9.5 Hz), 7.30 (1H, d, J=8.7 Hz), 7.93-8.03 (2H, m), 11.06 (1H,s).

Example 264 Production of1-tert-butyl-N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]-3-methyl-1H-pyrazole-5-carboxamide

To a solution ofN-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(210 mg, 0.65 mmol) in N,N-dimethylacetamide (5 mL) was added a solutionof 1-tert-butyl-3-methyl-1H-pyrazole-5-carbonylchloride (160 mg, 0.78mmol) in N,N-dimethylacetamide (1 mL), and the mixture was stirred atroom temperature for 30 min. Ethyl acetate/tetrahydrofuran and saturatedaqueous sodium hydrogencarbonate solution were added to the mixture, theaqueous layer was extracted with ethyl acetate/tetrahydrofuran (×4).Combined organic layer was washed with water and saturated brine, driedover anhydrous sodium sulfate, and filtrated. The filtrate wasconcentrated under reduced pressure, and the residue was purified bysilica gel column chromatography (ethyl acetate/hexane=40/60→90/10) togive the title compound (14 mg, 4%) as a white solid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.74-0.88 (4H, m), 1.60 (9H, s), 1.86-1.98(1H, m), 2.19 (3H, s), 2.27 (3H, s), 6.45 (1H, s), 6.99-7.15 (2H, m),7.27-7.41 (2H, m), 7.91-7.97 (1H, m), 8.02 (1H, d, J=9.8 Hz), 10.05 (1H,s), 11.05 (1H, s).

Example 265 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]-1-(2-methoxyethyl)-3-methyl-1H-pyrazole-5-carboxamide

In the same manner as in Example 259 and using1-(2-methoxyethyl)-3-methyl-1H-pyrazole-5-carboxylic acid (150 mg, 0.80mmol), tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalylchloride (83 μL, 0.97 mmol),N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cycloprcpanecarboxamide(200 mg, 0.62 mmol) and N,N-dimethylacetamide (7 mL) as startingmaterials, the title compound (230 mg, 77%) was obtained as a pale-greensolid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.74-0.85 (4H, m), 1.85-1.98 (1H, m), 2.20(3H, s), 2.25 (3H, s), 3.17 (3H, s), 3.62 (2H, t, J=5.5 Hz), 4.56 (2H,t, J=5.5 Hz), 6.76 (1H, s), 7.04 (1H, d, J=9.5 Hz), 7.10 (1H, dd, J=8.3,2.3 Hz), 7.26 (1H, d, J=2.3 Hz), 7.34 (1H, d, J=8.3 Hz), 7.93 (1H, s),8.02 (1H, d, J=9.5 Hz), 9.82 (1H, s), 11.05 (1H, s).

Example 266 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]-2,4-dimethyl-1,3-thiazole-5-carboxamide

In the same manner as in Example 261 and using2,4-dimethyl-1,3-thiazole-5-carboxylic acid (130 mg, 0.80 mmol),N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(200 mg, 0.62 mmol), 1-hydroxybenzotriazole (110 mg, 0.80 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (150 mg,0.80 mmol), triethylamine (94 mg, 0.93 mmol) and N,N-dimethylformamide(5 mL) as starting materials, the title compound (120 mg, 41%) wasobtained as a pale-yellow solid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.75-0.84 (4H, m), 1.86-1.97 (1H, m), 2.26(3H, s), 2.57 (3H, s), 2.64 (3H, s), 7.03 (1H, d, J=9.5 Hz), 7.08 (1H,dd, J=8.3, 2.3 Hz), 7.30-7.37 (2H, m), 7.93 (1H, s), 8.02 (1H, d, J=9.5Hz), 9.62 (1H, s), 11.06 (1H, s).

Example 267 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-2,4-dimethyl-1,3-thiazole-5-carboxamide

In the same manner as in Example 261 and using2,4-dimethyl-1,3-thiazole-5-carboxylic acid (190 mg, 1.2 mmol),N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(200 mg, 0.62 mmol), 1-hydroxybenzotriazole (170 mg, 1.2 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (240 mg, 1.2mmol), N,N-diisopropylethylamine (240 mg, 1.9 mmol) andN,N-dimethylformamide (5 mL) as starting materials, the title compound(93 mg, 32%) was obtained as a pale-yellow solid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.76-0.85 (4H, m), 1.86-1.97 (1H, m), 2.56(3H, s), 2.65 (3H, s), 7.07 (1H, d, J=9.8 Hz), 7.14-7.23 (1H, m),7.33-7.44 (1H, m), 7.58 (1H, dd, J=6.2, 2.8 Hz), 7.94 (1H, s), 8.04 (1H,d, J=9.8 Hz), 9.94 (1H, s), 11.06 (1H, s).

Example 268 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-1-(2-methoxyethyl)-3-methyl-1H-pyrazole-5-carboxamide

In the same manner as in Example 259 and using1-(2-methoxyethyl)-3-methyl-1H-pyrazole-5-carboxylic acid (150 mg, 0.80mmol), tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalylchloride (83 μL, 0.97 mmol),N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(200 mg, 0.62 mmol) and N,N-dimethylacetamide (7 mL) as startingmaterials, the title compound (230 mg, 77%) was obtained as a whitesolid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.73-0.82 (4H, m), 1.85-1.97 (1H, m), 2.19(3H, s), 3.30 (3H, s), 3.63 (2H, t, J=5.7 Hz), 4.56 (2H, t, J=5.7 Hz),6.81 (1H, s), 7.07 (1H, d, J=9.5 Hz), 7.17-7.25 (1H, m), 7.35-7.44 (1H,m), 7.54 (1H, dd, J=6.2, 2.8 Hz), 7.94 (1H, s), 8.04 (1H, d, J=9.5 Hz),10.12 (1H, s), 11.06 (1H, s).

Example 269 Production ofN-(5-{[2-(acetylamino)imidazo[1,2-b]pyridazin-6-yl]oxy}-2-methylphenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide

In the same manner as in Example 264 and usingN-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]acetamide(840 mg, 2.8 mmol), 1,3-dimethyl-1H-pyrazole-5-carbonylchloride (540 mg,3.4 mmol) and N,N-dimethylacetamide (35 mL), the title compound (910 mg,77%) was obtained as a white solid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 2.05 (3H, s), 2.18 (3H, s), 2.25 (3H, s),3.98 (3H, s), 6.81 (1H, s), 7.04 (1H, d, J=9.8 Hz), 7.10 (1H, dd, J=8.3,2.7 Hz), 7.28 (1H, d, J=2.7 Hz), 7.35 (1H, d, J=8.3 Hz), 7.95 (1H, s),8.02 (1H, d, J=9.8 Hz), 9.79 (1H, s), 10.78 (1H, s).

Example 270 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]-4-methyl-1,3-oxazole-5-carboxamide

In the same manner as in Example 259 and using4-methyl-1,3-oxazole-5-carboxylic acid (77 mg, 0.60 mmol),tetrahydrofuran (10 mL), N,N-dimethylformamide (1 drop), oxalyl chloride(62 μL, 0.72 mmol),N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(150 mg, 0.46 mmol) and N,N-dimethylacetamide (7 mL) as startingmaterials, the title compound (170 mg, 83%) was obtained as a whitesolid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.73-0.87 (4H, m), 1.86-1.98 (1H, m), 2.25(3H, s), 2.41 (3H, s), 7.04 (1H, d, J=9.5 Hz), 7.09 (1H, dd, J=8.1, 2.5Hz), 7.29-7.39 (2H, m), 7.94 (1H, s), 8.03 (1H, d, J=9.5 Hz), 8.51 (1H,s), 9.82 (1H, s), 11.06 (1H, s).

Example 271 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]-2-methyl-1,3-oxazole-4-carboxamide

In the same manner as in Example 259 and using2-methyl-1,3-oxazole-4-carboxylic acid (77 mg, 0.60 mmol),tetrahydrofuran (10 mL), N,N-dimethylformamide (1 drop), oxalyl chloride(62 μL, 0.72 mmol),N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(150 mg, 0.46 mmol) and N,N-dimethylacetamide (7 mL) as startingmaterials, the title compound (150 mg, 74%) was obtained as a whitesolid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.73-0.85 (4H, m), 1.87-1.96 (1H, m), 2.27(3H, s), 2.51 (3H, s), 6.99-7.07 (2H, m), 7.32 (1H, d, J=8.7 Hz), 7.54(1H, d, J=2.7 Hz), 7.94 (1H, s), 8.02 (1H, d, J=9.8 Hz), 8.62 (1H, s),9.54 (1H, s), 11.06 (1H, s).

Example 272 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]-2,4-dimethyl-1,3-oxazole-5-carboxamide

In the same manner as in Example 259 and using2,4-dimethyl-1,3-oxazole-5-carboxylic acid (85 mg, 0.60 mmol),tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride(62 μL, 0.72 mmol),N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(150 mg, 0.46 mmol) and N,N-dimethylacetamide (7 mL) as startingmaterials, the title compound (170 mg, 81%) was obtained as a whitesolid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.76-0.84 (4H, m), 1.86-1.98 (1H, m), 2.24(3H, s), 2.34 (3H, s), 2.48 (3H, s), 7.03 (1H, d, J=9.5 Hz), 7.08 (1H,dd, J=8.3, 2.7 Hz), 7.29 (1H, d, J=2.7 Hz), 7.33 (1H, d, J=8.3 Hz), 7.94(1H, s), 8.02 (1H, d, J=9.5 Hz), 9.70 (1H, s), 11.06 (1H, s).

Example 273 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]-3-methyl-1H-pyrazole-5-carboxamide

In the same manner as in Example 261 and using3-methyl-1H-pyrazole-5-carboxylic acid (160 mg, 1.2 mmol),N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(200 mg, 0.62 mmol), 1-hydroxybenzotriazole (170 mg, 1.2 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (240 mg, 1.2mmol), triethylamine (190 mg, 1.9 mmol) and N,N-dimethylformamide (3 mL)as starting materials, the title compound (190 mg, 70%) was obtained asa white solid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.74-0.84 (4H, m), 1.87-1.97 (1H, m), 2.29(6H, s), 6.49 (1H, s), 6.99 (1H, dd, J=8.3, 2.7 Hz), 7.03 (1H, d, J=9.5Hz), 7.31 (1H, d, J=8.3 Hz), 7.68 (1H, d, J=2.7 Hz), 7.94 (1H, s), 8.02(1H, d, J=9.5 Hz), 9.36 (1H, s), 11.06 (1H, s), 13.09 (1H, s).

Example 274 Production ofN-{5-[(2-{[(2,2-difluorocyclopropyl)carbonyl]amino}imidazo[1,2-b]pyridazin-6-yl)oxy]-2-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide

In the same manner as in Example 259 and using2,2-difluorocyclopropanecarboxylic acid (88 mg, 0.60 mmol),tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride(74 μL, 0.86 mmol),N-{5-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]-2-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamidehydrochloride (250 mg, 0.60 mmol) and N,N-dimethylacetamide (7 mL) asstarting materials, the title compound (210 mg, 73%) was obtained as awhite solid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.95-2.09 (2H, m), 2.19 (3H, s), 2.25 (3H,s), 2.86-2.96 (1H, m), 3.98 (3H, s), 6.81 (1H, s), 7.05-7.13 (2H, m),7.29 (1H, d, J=2.3 Hz), 7.35 (1H, d, J=8.3 Hz), 7.96 (1H, s), 8.06 (1H,d, J=9.8 Hz), 9.79 (1H, s), 11.29 (1H, s).

Example 275 Production ofN-{5-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]-2-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamidehydrochloride

To a suspension ofN-(5-{[2-(acetylamino)imidazo[1,2-b]pyridazin-6-yl]oxy}-2-methylphenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide(310 mg, 0.73 mmol) in methanol (10 mL) was added 4N hydrochloricacid/ethyl acetate (10 mL, 40 mmol), and the mixture was stirred at roomtemperature for 16 hr. The solvent was evaporated under reducedpressure, and the residue was washed with ethyl acetate/tetrahydrofuran,and then with diethyl ether to give the title compound (240 mg, 78%) asa pale-yellow solid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 2.18 (3H, s), 2.27 (3H, s), 3.97 (3H, s),6.90 (1H, s), 7.12 (1H, dd, J=8.3, 2.3 Hz), 7.29-7.41 (3H, m), 7.45 (1H,s), 8.20 (1H, d, J=9.5 Hz), 9.94 (1H, s).

Example 276 Production of2-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)benzoicacid

To a solution of ethyl salicylate (1010 mg, 6.1 mmol) inN,N-dimethylformamide (8 mL) was added potassium tert-butoxide (840 mg,6.4 mmol) at 0° C., and the mixture was stirred at 0° C. for 5 min andat room temperature for 25 min. To the reaction mixture were addedN-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (1.0 g,3.1 mmol) and potassium carbonate (420 mg, 3.1 mmol), and the mixturewas stirred at 100° C. for 24 hr. The solvent was evaporated underreduced pressure, ethyl acetate/tetrahydrofuran and water were added tothe residue. The aqueous layer was extracted with ethylacetate/tetrahydrofuran (×3). Combined organic layer was washed withsaturated brine, dried over anhydrous sodium sulfate, and filtrated. Thefiltrate was concentrated under reduced pressure, and the residue waspurified by silica gel column chromatography (ethylacetate/hexane=40/60→90/10) to give ethyl2-({2[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)benzoate(200 mg, 18%) as a white solid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.74-0.83 (4H, m), 1.00 (3H, t, J=7.2 Hz),1.83-1.97 (1H, m), 4.08 (2H, q, J=7.2 Hz), 7.09 (1H, d, J=9.5 Hz),7.39-7.51 (2H, m), 7.69-7.76 (1H, m), 7.80 (1H, s), 7.95 (1H, dd, J=7.8,1.7 Hz), 8.03 (1H, d, J=9.5 Hz), 11.02 (1H, s).

To a solution of ethyl2-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)benzoate(200 mg, 0.54 mmol) in tetrahydrofuran (10 mL) was added 4N aqueoussodium hydroxide solution (1.5 mL), and the mixture was stirred at roomtemperature for 3 hr. 6N Hydrochloric acid (1.5 mL) and ethyl acetatewere added to the reaction mixture, and the aqueous layer was extractedwith ethyl acetate (×4). Combined organic layer was washed withsaturated brine, dried over anhydrous sodium sulfate, and filtrated. Thefiltrate was concentrated under reduced pressure, and the residue waswashed with ethyl acetate/hexane to give the title compound (130 mg,73%) as a white solid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.72-0.83 (4H, m), 1.84-1.96 (1H, m), 7.07(1H, d, J=9.6 Hz), 7.35-7.46 (2H, m), 7.66-7.73 (1H, m), 7.81 (1H, s),7.94 (1H, dd, J=7.7, 1.7 Hz), 8.00 (1H, d, J=9.6 Hz), 11.02 (1H, s).

Example 277 Production of2-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}thio)benzoicacid

A mixture of methyl 2-mercaptobenzoate (1030 mg, 6.1 mmol),N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (1.0 g,3.1 mmol), potassium carbonate (1050 mg, 7.6 mmol) andN,N-dimethylformamide (10 mL) was stirred at 80° C. for 7 hr. Themixture was evaporated under reduced pressure, and ethylacetate/tetrahydrofuran and water were added to the residue. The aqueouslayer was extracted with ethyl acetate/tetrahydrofuran (×3). Combinedorganic layer was washed with saturated brine, dried over anhydroussodium sulfate, and filtrated. The filtrate was concentrated underreduced pressure, and the residue was purified by silica gel columnchromatography (ethyl acetate/hexane=40/60→90/10) to give methyl2-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}thio)benzoate(200 mg, 18%) as a brown solid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.78-0.89 (4H, m), 1.90-2.00 (1H, m), 3.85(3H, s), 7.16 (1H, d, J=9.5 Hz), 7.28 (1H, d, J=8.0 Hz), 7.39-7.46 (1H,m), 7.48-7.55 (1H, m), 7.90-8.00 (2H, m), 8.21 (1H, s), 11.21 (1H, s).

In the same manner as in Example 276 and using methyl2-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}thio)benzoate(390 mg, 1.1 mmol) and 4N aqueous sodium hydroxide solution (2 mL) asstarting materials, the title compound (340 mg, 92%) was obtained as apale-yellow solid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.77-0.91 (4H, m), 1.88-2.02 (1H, m),7.15-7.21 (2H, m), 7.38 (1H, t, J=6.8 Hz), 7.43-7.50 (1H, m), 7.89-8.01(2H, m), 8.22 (1H, s), 11.21 (1H, s).

Example 278 Production of2-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}thio)-N-methylbenzamide

A mixture of2-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}thio)benzoicacid (120 mg, 0.35 mmol), a solution of methylamine in tetrahydrofuran(2M, 1 mL, 2.0 mmol),O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (200 mg, 0.53 mmol) and N,N-dimethylformamide (4 mL)was stirred at room temperature for 5 hr. The mixture was evaporatedunder reduced pressure, ethyl acetate/tetrahydrofuran and water wereadded to the residue, and the aqueous layer was extracted with ethylacetate/tetrahydrofuran (×4). Combined organic layer was washed withsaturated brine, dried over anhydrous sodium sulfate, and filtrated. Thefiltrate was concentrated under reduced pressure, and the residue waspurified by silica gel column chromatography (ethylacetate/hexane=40/60→90/10) to give the title compound (45 mg, 41%) as apale-yellow solid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.77-0.88 (4H, m), 1.89-1.97 (1H, m), 2.71(3H, d, J=4.5 Hz), 6.97 (1H, d, J=9.5 Hz), 7.38-7.46 (3H, m), 7.49-7.56(1H, m), 7.88 (1H, d, J=9.5 Hz), 8.15 (1H, s), 8.40 (1H, t, J=4.5 Hz),11.15 (1H, s).

Example 279 Production of1,3-dimethyl-N-{2-methyl-5-[(2-{[(1-methylcyclopropyl)carbonyl]amino}imidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-1H-pyrazole-5-carboxamide

To a solution of 1-methylcyclopropanecarboxylic acid (97 mg, 0.97 mmol)in tetrahydrofuran (1.5 mL) were added N,N-dimethylformamide (1 drop)and oxalyl chloride (83 μL, 0.97 mmol), and the mixture was stirred atroom temperature for 30 min. The reaction mixture was added to asolution ofN-{5-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]-2-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamidehydrochloride (200 mg, 0.48 mmol) in N,N-dimethylacetamide (5 mL), andthe mixture was stirred at room temperature for 1 hr. Ethylacetate/tetrahydrofuran and saturated aqueous sodium hydrogencarbonatesolution were added to the mixture, and the aqueous layer was extractedwith ethyl acetate/tetrahydrofuran (×4). Combined organic layer waswashed with water and saturated brine, dried over anhydrous sodiumsulfate, and filtrated. The filtrate was concentrated under reducedpressure, and the residue was purified by silica gel columnchromatography (ethyl acetate/hexane=30/70→100/0) to give the titlecompound (105 mg, 74%) as a white solid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.60-0.68 (2H, m), 1.09-1.15 (2H, m), 1.40(3H, s), 2.19 (3H, s), 2.25 (3H, s), 3.98 (3H, s), 6.81 (1H, s), 7.05(1H, d, J=9.6 Hz), 7.10 (1H, dd, J=8.7, 2.4 Hz), 7.28 (1H, d, J=2.4 Hz),7.35 (1H, d, J=8.7 Hz), 7.98 (1H, s), 8.02 (1H, d, J=9.6 Hz), 9.80 (1H,s), 10.15 (1H, s).

Example 280 Production of1,3-dimethyl-N-{2-methyl-5-[(2-{[(2-methylcyclopropyl)carbonyl]amino}imidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-1H-pyrazole-5-carboxamide

In the same manner as in Example 279 and using2-methylcyclopropanecarboxylic acid (97 mg, 0.97 mmol), tetrahydrofuran(1.5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (83 μL, 0.97mmol),N-{5-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]-2-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamidehydrochloride (200 mg, 0.48 mmol) and N,N-dimethylacetamide (5 mL) asstarting materials, the title compound (155 mg, 70%) was obtained as awhite solid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.58-0.69 (1H, m), 0.93-1.04 (1H, m),1.04-1.12 (3H, m), 1.17-1.28 (1H, m), 1.61-1.71 (1H, m), 2.20 (3H, s),2.25 (3H, s), 3.98 (3H, s), 6.81 (1H, s), 7.03 (1H, d, J=9.5 Hz), 7.09(1H, dd, J=8.3, 2.7 Hz), 7.27 (1H, d, J=2.7 Hz), 7.34 (1H, d, J=8.3 Hz),7.92 (1H, s), 8.02 (1H, d, J=9.5 Hz), 9.79 (1H, s), 10.97 (1H, s).

Example 281 Production ofN-[5-({2-[(cyclobutylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide

In the same manner as in Example 264 and usingN-{5-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]-2-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamidehydrochloride (200 mg, 0.48 mmol), cyclobutanecarbonyl chloride (86 mg,0.73 mmol) and N,N-dimethylacetamide (5 mL) as starting materials, thetitle compound (170 mg, 76%) was obtained as a white solid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.73-1.98 (3H, m), 2.01-2.22 (4H, m), 2.19(3H, s), 2.25 (3H, s), 3.99 (3H, s), 6.81 (1H, s), 7.04 (1H, d, J=9.8Hz), 7.10 (1H, dd, J=8.7, 2.4 Hz), 7.28 (1H, d, J=2.4 Hz), 7.35 (1H, d,J=8.7 Hz), 7.96-8.06 (2H, m), 9.81 (1H, s), 10.64 (1H, s).

Example 282 Production of1,3-dimethyl-N-[2-methyl-5-({2-[(3-methylbut-2-enoyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-1H-pyrazole-5-carboxamide

In the same manner as in Example 264 and usingN-{5-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]-2-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamidehydrochloride (200 mg, 0.48 mmol), 3-methylbut-2-enoylchloride (81 μL,0.73 mmol) and N,N-dimethylacetamide (5 mL) as starting materials, thetitle compound (150 mg, 68%) was obtained as a pale-yellow solid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.85 (3H, s), 2.17 (3H, d, J=0.8 Hz), 2.19(3H, s), 2.25 (3H, s), 3.98 (3H, s), 5.98 (1H, s), 6.81 (1H, s), 7.03(1H, d, J=9.6 Hz), 7.10 (1H, dd, J=8.5, 2.4 Hz), 7.28 (1H, d, J=2.4 Hz),7.35 (1H, d, J=8.5 Hz), 7.96-8.05 (2H, m), 9.81 (1H, s), 10.69 (1H, s).

Example 283 Production ofN-{5-[(2-{[(2E)-3-methoxyprop-2-enoyl]amino}imidazo[1,2-b]pyridazin-6-yl)oxy]-2-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide

In the same manner as in Example 279 and using (2E)-3-methoxyacrylicacid (99 mg, 0.97 mmol), tetrahydrofuran (1.5 mL), N,N-dimethylformamide(1 drop), oxalyl chloride (83 μL, 0.97 mmol),N-{5-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]-2-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamidehydrochloride (200 mg, 0.48 mmol) and N,N-dimethylacetamide (5 mL) asstarting materials, the title compound (63 mg, 28%) was obtained as awhite solid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 2.19 (3H, s), 2.25 (3H, s), 3.68 (3H, s),3.98 (3H, s), 5.68 (1H, d, J=12.2 Hz), 6.83 (1H, s), 7.04 (1H, d, J=9.6Hz), 7.10 (1H, dd, J=8.7, 2.6 Hz), 7.27 (1H, d, J=2.6 Hz), 7.35 (1H, d,J=8.7 Hz), 7.54 (1H, d, J=12.2 Hz), 7.96-8.07 (2H, m), 9.84 (1H, s),10.61 (1H, s).

Example 284 Production ofN-{5-[(2-{[(ethylamino)carbonyl]amino}imidazo[1,2-b]pyridazin-6-yl)oxy]-2-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide

To a solution ofN-{5-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]-2-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamidehydrochloride (200 mg, 0.48 mmol) in pyridine (3 mL) was added ethylisocyanate (380 μL, 4.8 mmol), and the mixture was stirred at roomtemperature for 2 hr. Ethyl acetate/tetrahydrofuran and water were addedto the reaction mixture, and the aqueous layer was extracted with ethylacetate/tetrahydrofuran (×3). Combined organic layer was washed withsaturated brine, dried over anhydrous sodium sulfate, and filtrated. Thefiltrate was concentrated under reduced pressure, and the residue waspurified by silica gel column chromatography (ethylacetate/hexane=30/70→100/0) to give the title compound (160 mg, 72%) asa pale-yellow solid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.05 (3H, t, J=7.2 Hz), 2.20 (3H, s), 2.24(3H, s), 3.06-3.18 (2H, m), 3.98 (3H, s), 6.47-6.55 (1H, m), 6.81 (1H,s), 6.97 (1H, d, J=9.6 Hz), 7.08 (1H, dd, J=8.7, 2.6 Hz), 7.26 (1H, d,J=2.6 Hz), 7.34 (1H, d, J=8.7 Hz), 7.70 (1H, s), 7.95 (1H, d, J=9.6 Hz),8.99 (1H, s), 9.80 (1H, s).

Example 285 Production of1,3-dimethyl-N-{2-methyl-5-[(2-{[(methylsulfonyl)acetyl]amino}imidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-1H-pyrazole-5-carboxamide

In the same manner as in Example 279 and using (methylsulfonyl)aceticacid (100 mg, 0.73 mmol), tetrahydrofuran (1.5 mL),N,N-dimethylformamide (1 drop), oxalyl chloride (63 μL, 0.73 mmol),N-{5-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]-2-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamidehydrochloride (200 mg, 0.48 mmol) and N,N-dimethylacetamide (5 mL) asstarting materials, the title compound (91 mg, 38%) was obtained as apale-yellow solid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 2.20 (3H, s), 2.25 (3H, s), 3.17 (3H, s),3.99 (3H, s), 4.37 (2H, s), 6.81 (1H, s), 7.07-7.14 (2H, m), 7.29 (1H,d, J=2.7 Hz), 7.35 (1H, d, J=8.7 Hz), 8.01 (1H, s), 8.08 (1H, d, J=9.5Hz), 9.79 (1H, s), 11.26 (1H, s).

Example 286 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-1-ethyl-3-methyl-1H-pyrazole-5-carboxamide

In the same manner as in Example 259 and using1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (120 mg, 0.79 mmol),tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride(89 μL, 1.0 mmol),N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(200 mg, 0.61 mmol) and N,N-dimethylacetamide (7 mL) as startingmaterials, the title compound (150 mg, 53%) was obtained as a whitesolid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.75-0.85 (4H, m), 1.29 (3H, t, J=7.0 Hz),1.86-1.97 (1H, m), 2.21 (3H, s), 4.40 (2H, q, J=7.0 Hz), 6.83 (1H, s),7.07 (1H, d, J=9.5 Hz), 7.16-7.25 (1H, m), 7.34-7.45 (1H, m), 7.54 (1H,dd, J=6.4, 3.0 Hz), 7.94 (1H, s), 8.04 (1H, d, J=9.5 Hz), 10.08 (1H, s),11.06 (1H, s).

Example 287 Production ofN-[5-({2-[(cyclcpropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-1-methyl-1H-pyrazole-5-carboxamide

In the same manner as in Example 259 and using1-methyl-1H-pyrazole-5-carboxylic acid (100 mg, 0.79 mmol),tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride(89 μL, 1.0 mmol),N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(200 mg, 0.61 mmol) and N,N-dimethylacetamide (7 mL) as startingmaterials, the title compound (180 mg, 68%) was obtained as a whitesolid. melting point 253° C.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.75-0.85 (4H, m), 1.87-1.98 (1H, m), 4.06(3H, s), 7.07 (1H, d, J=7.2 Hz), 7.09 (1H, s), 7.17-7.26 (1H, m),7.34-7.46 (1H, m), 7.50-7.56 (2H, m), 7.94 (1H, s), 8.04 (1H, d, J=9.8Hz), 10.19 (1H, s), 11.06 (1H, s).

Example 288 Production ofN-[5-({2-[(3-hydroxy-3-methylbutanoyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide

In the same manner as in Example 278 and using3-hydroxy-3-methylbutanoic acid (74 mg, 0.63 mmol),N-{5-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]-2-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamidehydrochloride (200 mg, 0.48 mmol),O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (240 mg, 0.63 mmol), N,N-diisopropylethylamine (190mg, 1.5 mmol) and N,N-dimethylformamide (7 mL) as starting materials,the title compound (150 mg, 66%) was obtained as a pale-yellow solid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.19 (6H, s), 2.19 (3H, s), 2.25 (3H, s),2.48 (2H, s), 3.98 (3H, s), 4.76 (1H, s), 6.81 (1H, s), 6.99-7.14 (2H,m), 7.28 (1H, d, J=2.3 Hz), 7.35 (1H, d, J=8.3 Hz), 7.94-8.06 (2H, m),9.79 (1H, s), 10.58 (1H, s).

Example 289 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-2,4-dimethyl-1,3-oxazole-5-carboxamide

In the same manner as in Example 259 and using2,4-dimethyl-1,3-oxazole-5-carboxylic acid (84 mg, 0.59 mmol),tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride(61 μL, 0.71 mmol),N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(150 mg, 0.46 mmol) and N,N-dimethylacetamide (7 mL) as startingmaterials, the title compound (140 mg, 67%) was obtained as a whitesolid. melting point 202° C.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.73-0.86 (4H, m), 1.84-1.98 (1H, m), 2.3.5(3H, s), 2.48 (3H, s), 7.07 (1H, d, J=9.6 Hz), 7.14-7.23 (1H, m), 7.39(1H, dd, J=10.0, 9.0 Hz), 7.56 (1H, dd, J=6.4, 3.0 Hz), 7.95 (1H, s),8.04 (1H, d, J=9.6 Hz), 9.95 (1H, s), 11.07 (1H, s).

Example 290 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-4-methyl-1,3-oxazole-5-carboxamide

In the same manner as in Example 259 and using4-methyl-1,3-oxazole-5-carboxylic acid (76 mg, 0.59 mmol),tetrahydrofuran (10 mL), N,N-dimethylformamide (1 drop), oxalyl chloride(61 μL, 0.71 mmol),N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(150 mg, 0.46 mmol) and N,N-dimethylacetamide (7 mL) as startingmaterial, the title compound (170 mg, 84%) was obtained as a whitesolid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.74-0.86 (4H, m), 1.85-1.97 (1H, m), 2.41(3H, s), 7.07 (1H, d, J=9.4 Hz), 7.16-7.25 (1H, m), 7.40 (1H, dd,J=10.0, 9.0 Hz), 7.57 (1H, dd, J=6.4, 3.0 Hz), 7.94 (1H, s), 8.04 (1H,d, J=9.4 Hz), 8.54 (1H, s), 10.10 (1H, s), 11.07 (1H, s).

Example 291 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]-1-ethyl-1H-pyrazole-5-carboxamide

In the same manner as in Example 259 and using1-ethyl-1H-pyrazole-5-carboxylic acid (110 mg, 0.80 mmol),tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride(83 μL, 0.97 mmol),N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(200 mg, 0.62 mmol) and N,N-dimethylacetamide (7 mL) as startingmaterials, the title compound (210 mg, 75%) was obtained as a whitesolid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.73-0.85 (4H, m), 1.32 (3H, t, J=7.2 Hz),1.86-1.96 (1H, m), 2.25 (3H, s), 4.50 (2H, q, J=7.2 Hz), 7.02-7.07 (2H,m), 7.11 (1H, dd, J=8.3, 2.4 Hz), 7.28 (1H, d, J=2.4 Hz), 7.36 (1H, d,J=8.3 Hz), 7.54 (1H, d, J=2.1 Hz), 7.93 (1H, s), 8.03 (1H, d, J=10.0Hz), 9.92 (1H, s), 11.10 (1H, s).

Example 292 Production ofN-{5-[(2-{[(2-methoxycyclopropyl)carbonyl]amino}imidazo[1,2-b]pyridazin-6-yl)oxy]-2-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide

In the same manner as in Example 278 and using2-methoxycyclopropanecarboxylic acid (86 mg, 0.74 mmol),N-{5-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]-2-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamidehydrochloride (200 mg, 0.49 mmol),O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (280 mg, 0.74 mmol), N,N-diisopropylethylamine (190mg, 1.5 mmol) and N,N-dimethylformamide (7 mL) as starting materials,the title compound (83 mg, 35%) was obtained as a pale-yellow solid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.09-1.20 (2H, m), 2.03-2.13 (1H, m), 2.19(3H, s), 2.25 (3H, s), 3.30 (3H, s), 3.40-3.49 (1H, m), 3.97 (3H, s),6.81 (1H, s), 7.04 (1H, d, J=9.8 Hz), 7.09 (1H, dd, J=8.3, 2.7 Hz), 7.28(1H, d, J=2.7 Hz), 7.34 (1H, d, J=8.3 Hz), 7.91 (1H, s), 8.03 (1H, d,J=9.8 Hz), 9.79 (1H, s), 11.09 (1H, s).

Example 293 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]-4-methoxy-2-methyl-1,3-thiazole-5-carboxamide

In the same manner as in Example 259 and using4-methoxy-2-methyl-1,3-thiazole-5-carboxylic acid (120 mg, 0.70 mmol),tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride(120 μL, 1.4 mmol),N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(150 mg, 0.46 mmol) and N,N-dimethylacetamide (7 mL) as startingmaterials, the title compound (120 mg, 53%) was obtained as a whitesolid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.74-0.85 (4H, m), 1.88-1.98 (1H, m), 2.32(3H, s), 2.65 (3H, s), 4.18 (3H, s), 6.96 (1H, dd, J=8.3, 2.7 Hz), 7.03(1H, d, J=9.8 Hz), 7.33 (1H, d, J=8.3 Hz), 7.93 (1H, s), 7.97 (1H, d,J=2.7 Hz), 8.02 (1H, d, J=9.8 Hz), 9.05 (1H, s), 11.06 (1H, s).

Example 294 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-3-methoxy-1-methyl-1H-pyrazole-4-carboxamide

In the same manner as in Example 259 and using3-methoxy-1-methyl-1H-pyrazole-4-carboxylic acid (93 mg, 0.60 mmol),tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride(61 μL, 0.72 mmol),N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(150 mg, 0.46 mmol) and N,N-dimethylacetamide (7 mL) as startingmaterials, the title compound (59 mg, 28%) was obtained as a whitesolid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.74-0.85 (4H, m), 1.86-1.97 (1H, m), 3.75(3H, s), 4.01 (3H, s), 6.97-7.09 (2H, m), 7.33-7.44 (1H, m), 7.94 (1H,s), 8.04 (1H, d, J=9.8 Hz), 8.11-8.19 (2H, m), 8.94 (1H, d, J=2.7 Hz),11.07 (1H, s).

Example 295 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-4-methoxy-2-methyl-1,3-thiazole-5-carboxamide

In the same manner as in Example 259 and using4-methoxy-2-methyl-1,3-thiazole-5-carboxylic acid (100 mg, 0.60 mmol),tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride(61 μL, 0.72 mmol),N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(150 mg, 0.46 mmol) and N,N-dimethylacetamide (7 mL) as startingmaterials, the title compound (89 mg, 40%) was obtained as a whitesolid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.74-0.84 (4H, m), 1.88-1.96 (1H, m),2.64-2.68 (3H, m), 4.18 (3H, s), 7.03-7.12 (2H, m), 7.42 (1H, dd,J=10.6, 9.1 Hz), 7.93 (1H, s), 8.01-8.09 (2H, m), 9.27 (1H, s), 11.06(1H, s).

Example 296 Production of1,3-dimethyl-N-[2-methyl-5-({2-[(oxirane-2-ylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-1H-pyrazole-5-carboxamide

In the same manner as in Example 279 and using oxirane-2-carboxylic acid(54 mg, 0.62 mmol), tetrahydrofuran (1.5 mL), N,N-dimethylformamide (1drop), oxalyl chloride (53 μL, 0.62 mmol),N-{5-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]-2-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamidehydrochloride (170 mg, 0.41 mmol) and N,N-dimethylacetamide (5 mL) asstarting materials, the title compound (96 mg, 52%) was obtained as awhite solid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 2.19 (3H, s), 2.25 (3H, s), 2.88-2.99 (2H,m), 3.64-3.70 (1H, m), 3.97 (3H, s), 6.81 (1H, s), 7.04-7.16 (2H, m),7.29 (1H, d, J=2.7 Hz), 7.35 (1H, d, J=8.3 Hz), 7.99 (1H, s), 8.07 (1H,d, J=9.8 Hz), 9.79 (1H, br. s), 11.30 (1H, br. s).

Example 297 Production of methyl2-({[6-(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]amino}carbonyl)cyclopropanecarboxylate

In the same manner as in Example 279 and using2-(methoxycarbonyl)cyclopropanecarboxylic acid (140 mg, 0.78 mmol),tetrahydrofuran (1.5 mL), N,N-dimethylformamide (1 drop), oxalylchloride (69 μL, 0.8 mmol),N-{5-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]-2-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamidehydrochloride (250 mg, 0.6 mmol) and N,N-dimethylacetamide (5 mL) asstarting materials, the title compound (75 mg, 25%) was obtained as awhite solid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.19-1.29 (2H, m), 1.39-1.47 (1H, m), 2.19(3H, s), 2.24 (3H, s), 2.25-2.33 (1H, m), 3.51 (3H, s), 3.97 (3H, s),6.80 (1H, s), 7.04 (1H, d, J=9.8 Hz), 7.09 (1H, dd, J=8.3, 2.7 Hz), 7.27(1H, d, J=2.7 Hz), 7.34 (1H, d, J=8.3 Hz), 7.90 (1H, s), 8.03 (1H, d,J=9.8 Hz), 9.79 (1H, s), 11.10 (1H, s).

Example 298 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]-4-methyl-1,3-thiazole-5-carboxamide

In the same manner as in Example 259 and using4-methyl-1,3-thiazole-5-carboxylic acid (86 mg, 0.60 mmol),tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride(100 μL, 1.2 mmol),N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(150 mg, 0.46 mmol) and N,N-dimethylacetamide (7 mL) as startingmaterials, the title compound (170 mg, 80%) was obtained as a whitesolid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.74-0.85 (4H, m), 1.85-1.97 (1H, m), 2.26(3H, s), 2.65 (3H, s), 7.04 (1H, d, J=9.8 Hz), 7.09 (1H, dd, J=8.3, 2.7Hz), 7.30-7.39 (2H, m), 7.94 (1H, s), 8.03 (1H, d, J=9.8 Hz), 9.12 (1H,s), 9.80 (1H, s), 11.06 (1H, s).

Example 299 Production of1-({[6-(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]amino}carbonyl)cyclopropylacetate

In the same manner as in Example 279 and using1-acetoxycyclopropanecarboxylic acid (90 mg, 0.63 mmol), tetrahydrofuran(1.5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (54 μL, 0.63mmol),N-{5-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]-2-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamidehydrochloride (200 mg, 0.48 mmol) and N,N-dimethylacetamide (5 mL) asstarting materials, the title compound (180 mg, 74%) was obtained as awhite solid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.11-1.19 (2H, m), 1.42-1.48 (2H, m), 2.10(3H, s), 2.19 (3H, s), 2.25 (3H, s), 3.98 (3H, s), 6.81 (1H, s), 7.06(1H, d, J=9.8 Hz), 7.10 (1H, dd, J=8.3, 2.7 Hz), 7.28 (1H, d, J=2.7 Hz),7.35 (1H, d, J=8.3 Hz), 7.99 (1H, s), 8.03 (1H, d, J=9.8 Hz), 9.79 (1H,br. s), 10.87 (1H, br. s).

Example 300 Production ofN-{5-[(2-{[(1-hydroxycyclopropyl)carbonyl]amino}imidazo[1,2-b]pyridazin-6-yl)oxy]-2-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide

To a solution of1-({[6-(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]amino}carbonyl)cyclopropylacetate (130 mg, 0.25 mmol) in tetrahydrofuran (2 mL) was added 1Naqueous sodium hydroxide solution (2 mL), and the mixture was stirred atroom temperature for 2 hr. 1N Hydrochloric acid (2.5 mL) and ethylacetate were added to the reaction mixture, and the aqueous layer wasextracted with ethyl acetate (×3). Combined organic layer was washedwith saturated brine, dried over anhydrous sodium sulfate, andfiltrated. The filtrate was concentrated under reduced pressure, and theresidue was washed with ethyl acetate/hexane to give the title compound(99 mg, 86%) as a pale-yellow solid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.96-1.03 (2H, m), 1.13-1.22 (2H, m), 2.19(3H, s), 2.26 (3H, s), 3.97 (3H, s), 6.63 (1H, br. s), 6.81 (1H, s),7.03-7.14 (2H, m), 7.29 (1H, d, J=2.7 Hz), 7.35 (1H, d, J=8.3 Hz), 7.98(1H, s), 8.06 (1H, d, J=9.8 Hz), 9.79 (2H, br. s).

Example 301 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]-5-methyl-1,3-thiazole-4-carboxamide

In the same manner as in Example 259 and using5-methyl-1,3-thiazole-4-carboxylic acid (74 mg, 0.52 mmol),tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride(170 μL, 2.0 mmol),N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cycloprcpanecarboxamide(130 mg, 0.40 mmol) and N,N-dimethylacetamide (7 mL) as startingmaterials, the title compound (110 mg, 60%) was obtained as a whitesolid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.76-0.84 (4H, m), 1.85-1.96 (1H, m), 2.31(3H, s), 2.78 (3H, s), 6.96-7.09 (2H, m), 7.34 (1H, d, J=8.7 Hz), 7.79(1H, d, J=2.4 Hz), 7.94 (1H, s), 8.03 (1H, d, J=10.2 Hz), 9.02 (1H, s),9.79 (1H, s), 11.07 (1H, s).

Example 302 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]-3-methoxy-1-methyl-1H-pyrazole-5-carboxamide

In the same manner as in Example 259 and using3-methoxy-1-methyl-1H-pyrazole-5-carboxylic acid (80 mg, 0.52 mmol),tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride(170 μL, 2.0 mmol),N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(130 mg, 0.40 mmol) and N,N-dimethylacetamide (7 mL) as startingmaterials, the title compound (160 mg, 85%) was obtained as a whitesolid. melting point 224° C.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.72-0.86 (4H, m), 1.86-1.97 (1H, m), 2.24(3H, s), 3.80 (3H, s), 3.90 (3H, s), 6.46 (1H, s), 7.04 (1H, d, J=9.6Hz), 7.10 (1H, dd, J=8.7, 2.6 Hz), 7.26 (1H, d, J=2.6 Hz), 7.35 (1H, d,J=8.7 Hz), 7.93 (1H, s), 8.03 (1H, d, J=9.6 Hz), 9.86 (1H, s), 11.07(1H, s).

Example 303 Production ofN-(5-{[2-(but-2-ynoylamino)imidazo[1,2-b]pyridazin-6-yl]oxy}-2-methylphenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide

In the same manner as in Example 279 and using but-2-ynoic acid (46 mg,0.54 mmol), tetrahydrofuran (1.5 mL), N,N-dimethylformamide (1 drop),oxalyl chloride (47 μL, 0.54 mmol),N-{5-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]-2-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamidehydrochloride (150 mg, 0.36 mmol) and N,N-dimethylacetamide (5 mL) asstarting materials, the title compound (60 mg, 37%) was obtained as awhite solid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 2.03 (3H, s), 2.19 (3H, s), 2.25 (3H, s),3.98 (3H, s), 6.81 (1H, s), 7.03-7.14 (2H, m), 7.28 (1H, d, J=2.4 Hz),7.35 (1H, d, J=8.5 Hz), 7.94 (1H, s), 8.06 (1H, d, J=9.6 Hz), 9.81 (1H,br. s), 11.48 (1H, br. s).

Example 304 Production ofN-(5-{[2-({[2-(hydroxymethyl)cyclopropyl]carbonyl}amino)imidazo[1,2-b]pyridazin-6-yl]oxy}-2-methylphenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide

To a suspension of calcium chloride (135 mg, 1.1 mmol) intetrahydrofuran/ethanol (2/1, 1 mL) was added a solution of sodiumborohydride (92 mg, 2.2 mmol) and methyl2-({[6-(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]amino}carbonyl)cyclopropanecarboxylate(180 mg, 0.37 mmol) in tetrahydrofuran/ethanol (2/1, 1 mL), and themixture was stirred at room temperature for 18 hr. Saturated aqueousammonium chloride solution and ethyl acetate were added to the reactionmixture, and the aqueous layer was extracted with ethyl acetate (×3).Combined organic layer was washed with saturated brine, dried overanhydrous sodium sulfate, and filtrated. The filtrate was concentratedunder reduced pressure, and the residue was purified by silica gelcolumn chromatography (ethyl acetate/hexane=40/60→100/0, and thenmethanol/ethyl acetate=0/100→5/95) to give the title compound (35 mg,20%) as a white solid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.83-1.04 (2H, m), 1.37-1.49 (1H, m),1.94-2.05 (1H, m), 2.19 (3H, s), 2.25 (3H, s), 3.41-3.53 (1H, m),3.56-3.66 (1H, m), 3.97 (3H, s), 4.44 (1H, t, J=5.2 Hz), 6.81 (1H, s),7.03 (1H, d, J=9.6 Hz), 7.09 (1H, dd, J=8.5, 2.6 Hz), 7.27 (1H, d, J=2.6Hz), 7.34 (1H, d, J=8.5 Hz), 7.95 (1H, s), 8.03 (1H, d, J=9.6 Hz), 9.80(1H, s), 10.99 (1H, s).

Example 305 Production ofN-(5-{[2-({[2-(1-hydroxy-1-methylethyl)cyclopropyl]carbonyl}amino)imidazo[1,2-b]pyridazin-6-yl]oxy}-2-methylphenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide

To a solution of methyl2-({[6-(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]amino}carbonyl)cyclopropanecarboxylate(250 mg, 0.49 mmol) in tetrahydrofuran (5 mL) was added a solution ofiodo(methyl)magnesium in diethyl ether (2M, 540 μL, 1.1 mmol) at 0° C.,and the mixture was stirred at room temperature for 1 hr. 0.5NHydrochloric acid (3 mL) and ethyl acetate were added to the reactionmixture, and the aqueous layer was extracted with ethyl acetate (×3).Combined organic layer was washed with saturated brine, dried overanhydrous sodium sulfate, and filtrated. The filtrate was concentratedunder reduced pressure, and the residue was washed with ethylacetate/hexane to give the title compound (190 mg, 78%) as a pale-greensolid.

¹H-NMR (CDCl₃, 300 MHz) δ 1.35-1.46 (1H, m), 1.67 (3H, s), 1.69-1.78(1H, m), 2.06-2.23 (2H, m), 2.30 (3H, s), 2.34 (3H, s), 3.70 (3H, s),4.12 (3H, s), 6.43 (1H, s), 6.85 (1H, d, J=9.6 Hz), 6.97 (1H, dd, J=8.3,2.4 Hz), 7.24-7.28 (1H, m), 7.58 (1H, s), 7.73 (1H, d, J=9.6 Hz), 7.94(1H, m), 8.13 (1H, s), 8.97 (1H, s).

Example 306 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]-3-ethyl-1-methyl-1H-pyrazole-5-carboxamide

In the same manner as in Example 259 and using3-ethyl-1-methyl-1H-pyrazole-5-carboxylic acid (120 mg, 0.80 mmol),tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride(170 μL, 2.0 mmol),N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(200 mg, 0.62 mmol) and N,N-dimethylacetamide (7 mL) as startingmaterials, the title compound (190 mg, 68%) was obtained as a whitesolid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.73-0.86 (4H, m), 1.19 (3H, t, J=7.8 Hz),1.87-1.97 (1H, m), 2.25 (3H, s), 2.57 (2H, q, J=7.8 Hz), 3.99 (3H, s),6.85 (1H, s), 7.04 (1H, d, J=9.5 Hz), 7.10 (1H, d, J=8.3 Hz), 7.27 (1H,s), 7.35 (1H, d, J=8.3 Hz), 7.94 (1H, s), 8.03 (1H, d, J=9.5 Hz), 9.81(1H, s), 11.06 (1H, s).

Example 307 Production of2-chloro-N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]-4-methyl-1,3-thiazole-5-carboxamide

In the same manner as in Example 259 and using2-chloro-4-methyl-1,3-thiazole-5-carboxylic acid (140 mg, 0.80 mmol),tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride(170 μL, 2.0 mmol),N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(200 mg, 0.62 mmol) and N,N-dimethylacetamide (7 mL) as startingmaterials, the title compound (270 mg, 91%) was obtained as a pale-greensolid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.74-0.85 (4H, m), 1.86-1.96 (1H, m), 2.25(3H, s), 2.58 (3H, s), 7.04 (1H, d, J=9.5 Hz), 7.10 (1H, dd, J=8.3, 2.3Hz), 7.31-7.38 (2H, m), 7.93 (1H, s), 8.03 (1H, d, J=9.5 Hz), 9.86 (1H,s), 11.06 (1H, s).

Example 308 Production of2-chloro-N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-4-methyl-1,3-thiazole-5-carboxamide

In the same manner as in Example 259 and using2-chloro-4-methyl-1,3-thiazole-5-carboxylic acid (140 mg, 0.80 mmol),tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride(140 μL, 1.6 mmol),N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(200 mg, 0.61 mmol) and N,N-dimethylacetamide (7 mL) as startingmaterials, the title compound (230 mg, 78%) was obtained as a pale-greensolid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.75-0.86 (4H, m), 1.85-1.97 (1H, m), 2.58(3H, s), 7.08 (1H, d, J=9.4 Hz), 7.17-7.26 (1H, m), 7.41 (1H, dd,J=10.0, 9.0 Hz), 7.59 (1H, dd, J=6.3, 2.9 Hz), 7.94 (1H, s), 8.05 (1H,d, J=9.4 Hz), 10.23 (1H, s), 11.08 (1H, s).

Example 309 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]-1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide

In the same manner as in Example 259 and using1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (160 mg, 0.80mmol), tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalylchloride (170 μL, 2.0 mmol),N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(200 mg, 0.62 mmol) and N,N-dimethylacetamide (7 mL) as startingmaterials, the title compound (240 mg, 76%) was obtained as a whitesolid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.74-0.86 (4H, m), 1.86-1.97 (1H, m), 2.27(3H, s), 4.15 (3H, s), 7.05 (1H, d, J=9.6 Hz), 7.13 (1H, dd, J=8.3, 2.6Hz), 7.30 (1H, d, J=2.6 Hz), 7.37 (1H, d, J=8.3 Hz), 7.49 (1H, s), 7.94(1H, s), 8.04 (1H, d, J=9.6 Hz), 10.13 (1H, s), 11.08 (1H, s).

Example 310 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide

In the same manner as in Example 259 and using1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (150 mg, 0.79mmol), tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalylchloride (140 μL, 1.6 mmol),N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(200 mg, 0.61 mmol) and N,N-dimethylacetamide (7 mL) as startingmaterials, the title compound (240 mg, 77%) was obtained as a whitesolid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.71-0.85 (4H, m), 1.85-1.97 (1H, m), 4.15(3H, s), 7.09 (1H, d, J=9.4 Hz), 7.21-7.28 (1H, m), 7.39-7.47 (1H, m),7.54 (1H, s), 7.58 (1H, dd, J=6.3, 2.9 Hz), 7.95 (1H, s), 8.05 (1H, d,J=9.4 Hz), 10.45 (1H, s), 11.08 (1H, s).

Example 311 Production of4-chloro-N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]-1-methyl-1H-pyrazole-3-carboxamide

In the same manner as in Example 259 and using4-chloro-1-methyl-1H-pyrazole-3-carboxylic acid (130 mg, 0.80 mmol),tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride(170 μL, 2.0 mmol),N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(200 mg, 0.62 mmol) and N,N-dimethylacetamide (7 mL) as startingmaterials, the title compound (235 mg, 82%) was obtained as a whitesolid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.74-0.84 (4H, m), 1.87-1.96 (1H, m), 2.27(3H, s), 3.93 (3H, s), 6.99-7.08 (2H, m), 7.32 (1H, d, J=8.7 Hz), 7.52(1H, d, J=2.6 Hz), 7.95 (1H, s), 8.03 (1H, d, J=10.2 Hz), 8.12 (1H, s),9.54 (1H, s), 11.07 (1H, s).

Example 312 Production of4-chloro-N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-1-methyl-1H-pyrazole-3-carboxamide

In the same manner as in Example 259 and using4-chloro-1-methyl-1H-pyrazole-3-carboxylic acid (130 mg, 0.79 mmol),tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride(170 μL, 2.0 mmol),N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(200 mg, 0.61 mmol) and N,N-dimethylacetamide (7 mL) as startingmaterials, the title compound (230 mg, 80%) was obtained as a whitesolid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.76-0.84 (4H, m), 1.86-1.97 (1H, m), 3.94(3H, s), 7.08 (1H, d, J=9.6 Hz), 7.10-7.18 (1H, m), 7.39 (1H, dd,J=10.4, 9.0 Hz), 7.80 (1H, dd, J=6.5, 2.9 Hz), 7.95 (1H, s), 8.05 (1H,d, J=9.6 Hz), 8.14 (1H, s), 9.68 (1H, s), 11.08 (1H, s).

Example 313 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]-2-ethyl-4-methyl-1,3-oxazole-5-carboxamide

In the same manner as in Example 259 and using2-ethyl-4-methyl-1,3-oxazole-5-carboxylic acid (230 mg, 1.5 mmol),tetrahydrofuran (6 mL), N,N-dimethylformamide (1 drop), oxalyl chloride(520 μL, 6.0 mmol),N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(400 mg, 1.2 mmol) and N,N-dimethylacetamide (10 mL) as startingmaterials, the title compound (390 mg, 69%) was obtained as a whitesolid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.74-0.85 (4H, m), 1.29 (3H, t, J=7.6 Hz),1.92 (1H, m), 2.24 (3H, s), 2.36 (3H, s), 2.81 (2H, q, J=7.6 Hz), 7.04(1H, d, J=9.5 Hz), 7.08 (1H, dd, J=8.3, 2.7 Hz), 7.26-7.37 (2H, m), 7.94(1H, s), 8.03 (1H, d, J=9.5 Hz), 9.71 (1H, s), 11.07 (1H, s).

Example 314 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-2-ethyl-4-methyl-1,3-oxazole-5-carboxamide

In the same manner as in Example 259 and using2-ethyl-4-methyl-1,3-oxazole-5-carboxylic acid (230 mg, 1.5 mmol),tetrahydrofuran (6 mL), N,N-dimethylformamide (1 drop), oxalyl chloride(520 μL, 6.0 mmol),N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(400 mg, 1.2 mmol) and N,N-dimethylacetamide (10 mL) as startingmaterials, the title compound (400 mg, 70%) was obtained as a whitesolid. melting point 228° C.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.74-0.85 (4H, m), 1.29 (3H, t, J=7.6 Hz),1.83-1.95 (1H, m), 2.36 (3H, s), 2.82 (2H, q, J=7.6 Hz), 7.07 (1H, d,J=9.8 Hz), 7.16-7.25 (1H, m), 7.33-7.44 (1H, m), 7.56 (1H, dd, J=6.2,2.8 Hz), 7.94 (1H, s), 8.04 (1H, d, J=9.8 Hz), 9.95 (1H, s), 11.07 (1H,s).

Example 315 Production of3-chloro-N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]-1-methyl-1H-pyrazole-5-carboxamide

In the same manner as in Example 259 and using3-chloro-1-methyl-1H-pyrazole-5-carboxylic acid (60 mg, 0.37 mmol),tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride(130 μL, 1.5 mmol),N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(100 mg, 0.31 mmol) and N,N-dimethylacetamide (5 mL) as startingmaterials, the title compound (110 mg, 74%) was obtained as a whitesolid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.01-0.15 (4H, m), 1.14-1.27 (1H, m), 1.54(3H, s), 1.80 (3H, s), 6.27-6.46 (3H, m), 6.58 (1H, d, J=2.4 Hz), 6.65(1H, d, J=8.5 Hz), 7.22 (1H, s), 7.33 (1H, d, J=9.6 Hz), 9.30 (1H, br.s), 10.37 (1H, s).

Example 316 Production of3-chloro-N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-1-methyl-1H-pyrazole-5-carboxamide

In the same manner as in Example 259 and using3-chloro-1-methyl-1H-pyrazole-5-carboxylic acid (59 mg, 0.37 mmol),tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride(130 μL, 1.5 mmol),N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(100 mg, 0.31 mmol) and N,N-dimethylacetamide (5 mL) as startingmaterials, the title compound (100 mg, 71%) was obtained as a whitesolid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.72-0.85 (4H, m), 1.84-1.97 (1H, m), 4.03(3H, s), 7.02-7.14 (2H, m), 7.19-7.28 (1H, m), 7.37-7.47 (1H, m), 7.56(1H, dd, J=6.3, 2.9 Hz), 7.94 (1H, s), 8.05 (1H, d, J=9.6 Hz), 10.33(1H, br. s), 11.08 (1H, s).

Example 317 Production ofN-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}amino)phenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide

A mixture ofN-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (330 mg,1.0 mmol), N-(3-aminophenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide (280mg, 1.2 mmol), tris(dibenzylideneacetone)dipalladium (0) (46 mg, 0.050mmol), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (48mg, 0.10 mmol), potassium tert-butoxide (170 mg, 1.5 mmol) andtert-butanol was heated under reflux for 2 days. Ethylacetate/tetrahydrofuran and saturated aqueous sodium hydrogencarbonatesolution were added to the mixture, the aqueous layer was extracted withethyl acetate/tetrahydrofuran (×4). Combined organic layer was washedwith saturated brine, dried over anhydrous sodium sulfate, andfiltrated. The filtrate was concentrated under reduced pressure, and theresidue was purified by silica gel column chromatography (ethylacetate/hexane=30/70→100/0) to give the title compound (37 mg, 9%) as abrown solid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.74-0.88 (4H, m), 1.86-1.98 (1H, m), 2.22(3H, s), 4.01 (3H, s), 6.85 (1H, s), 6.89 (1H, d, J=9.6 Hz), 7.24-7.36(2H, m), 7.45-7.53 (1H, m), 7.75 (1H, d, J=9.6 Hz), 8.00 (1H, s), 8.21(1H, s), 9.37 (1H, s), 10.15 (1H, s), 10.93 (1H, s).

Example 318 Production of4-chloro-N-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-3-(trifluoromethyl)benzamide

To a solution ofN-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(100 mg, 0.32 mmol) in N,N-dimethylformamide (6.0 mL) were added4-chloro-3-(trifluoromethyl)benzoic acid (73 mg, 0.32 mmol),N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (65 mg,0.34 mmol) and 1-hydroxybenzotriazole (46 mg, 0.34 mmol), and themixture was stirred at room temperature overnight. The reaction mixturewas diluted with water and extracted with ethyl acetate. The organiclayer was washed with saturated brine, dried over anhydrous sodiumsulfate, and filtrated. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography (ethyl acetate/hexane=30/70→80/20) and precipitated fromethyl acetate/diisopropyl ether to give the title compound (130 mg, 77%)as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.64-0.93 (4H, m), 1.79-2.04 (1H, m),6.99-7.13 (2H, m), 7.46 (1H, t, J=8.1 Hz), 7.59-7.69 (1H, m), 7.71 (1H,t, J=2.1 Hz), 7.93 (1H, d, J=8.4 Hz), 7.98 (1H, s), 8.06 (1H, d, J=9.6Hz), 8.24 (1H, dd, J=8.4, 2.1 Hz), 8.37 (1H, d, J=2.1 Hz), 10.64 (1H,s), 11.09 (1H, s).

Example 319 Production ofN-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-3-(trifluoromethyl)benzamide

UsingN-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(80 mg, 0.26 mmol), 3-(trifluoromethyl)benzoic acid (54 mg, 0.29 mmol),N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (55 mg,0.29 mmol), 1-hydroxybenzotriazole (39 mg, 0.29 mmol) andN,N-dimethylformamide (5.0 mL) as starting materials and in the samemanner as in Example 318, the title compound (86 mg, 69%) was obtainedas a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.72-0.89 (4H, m), 1.84-2.03 (1H, m),6.98-7.15 (2H, m), 7.46 (1H, t, J=8.1 Hz), 7.60-7.70 (1H, m), 7.73 (1H,t, J=2.1 Hz), 7.79 (1H, t, J=7.8 Hz), 7.91-8.02 (2H, m), 8.06 (1H, d,J=9.6 Hz), 8.19-8.34 (2H, m), 10.59 (1H, s), 11.09 (1H, s).

Example 320 Production of3-(1-cyano-1-methylethyl)-N-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]benzamide

UsingN-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(100 mg, 0.32 mmol), 3-(1-cyano-1-methylethyl)benzoic acid (62 mg, 0.33mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride(65 mg, 0.34 mmol), 1-hydroxybenzotriazole (46 mg, 0.34 mmol) andN,N-dimethylformamide (5.0 mL) as starting materials and in the samemanner as in Example 318, the title compound (120 mg, 77%) was obtainedas a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.73-0.86 (4H, m), 1.74 (6H, s), 1.83-1.98(1H, m), 6.99-7.04 (1H, m), 7.08 (1H, d, J=9.6 Hz), 7.45 (1H, t, J=8.1Hz), 7.54-7.69 (2H, m), 7.69-7.80 (2H, m), 7.92 (1H, dt, J=7.8, 1.2 Hz),7.98 (1H, s), 8.00-8.10 (2H, m), 10.45 (1H, s), 11.09 (1H, s).

Example 321 Production ofN-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-4-(trifluoromethyl)benzamide

UsingN-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(100 mg, 0.32 mmol), 4-(trifluoromethyl)benzoic acid (63 mg, 0.33 mmol),N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (65 mg,0.34 mmol), 1-hydroxybenzotriazole (46 mg, 0.34 mmol) andN,N-dimethylformamide (5.0 mL) as starting materials and in the samemanner as in Example 318, the title compound (110 mg, 68%) was obtainedas a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.62-0.94 (4H, m), 1.76-2.06 (1H, m),6.99-7.05 (1H, m), 7.08 (1H, d, J=9.6 Hz), 7.45 (1H, t, J=8.1 Hz),7.63-7.71 (1H, m), 7.74 (1H, t, J=2.1 Hz), 7.92 (2H, d, J=8.2 Hz), 7.98(1H, s), 8.06 (1H, d, J=9.6 Hz), 8.13 (2H, d, J=8.2 Hz), 10.60 (1H, s),11.09 (1H, s).

Example 322 Production of4-chloro-N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]-3-(trifluoromethyl)benzamide

UsingN-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(80 mg, 0.25 mmol), 4-chloro-3-(trifluoromethyl)benzoic acid (57 mg,0.25 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimidehydrochloride (50 mg, 0.26 mmol), 1-hydroxybenzotriazole (35 mg, 0.26mmol) and N,N-dimethylformamide (4.0 mL) as starting materials and inthe same manner as in Example 318, the title compound (83 mg, 63%) wasobtained as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.73-0.85 (4H, m), 1.84-1.97 (1H, m), 2.26(3H, s), 7.05 (1H, d, J=9.6 Hz), 7.12 (1H, dd, J=8.4, 2.7 Hz), 7.30 (1H,d, J=2.7 Hz), 7.36 (1H, d, J=8.4 Hz), 7.86-7.97 (2H, m), 8.03 (1H, d,J=9.6 Hz), 8.25 (1H, dd, J=8.4, 1.8 Hz), 8.39 (1H, d, J=1.8 Hz), 10.26(1H, s), 11.07 (1H, s).

Example 323 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]-3-(trifluoromethyl)benzamide

UsingN-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(80 mg, 0.25 mmol), 3-(trifluoromethyl)benzoic acid (57 mg, 0.25 mmol),N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (50 mg,0.26 mmol), 1-hydroxybenzotriazole (35 mg, 0.26 mmol) andN,N-dimethylformamide (4.0 mL) as starting materials and in the samemanner as in Example 318, the title compound (83 mg, 63%) was obtainedas a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.72-0.86 (4H, m), 1.85-1.99 (1H, m), 2.27(3H, s), 7.05 (1H, d, J=9.6 Hz), 7.11 (1H, dd, J=8.4, 2.4 Hz), 7.31 (1H,d, J=2.4 Hz), 7.36 (1H, d, J=8.6 Hz), 7.78 (1H, t, J=7.8 Hz), 7.90-8.00(2H, m), 8.03 (1H, d, J=9.6 Hz), 8.20-8.36 (2H, m), 10.21 (1H, s), 11.07(1H, s).

Example 324 Production ofN-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-5-(methylsulfonyl)thiophene-2-carboxamide

UsingN-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(100 mg, 0.32 mmol), 5-(methylsulfonyl)thiophene-2-carboxylic acid (47mg, 0.33 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimidehydrochloride (65 mg, 0.34 mmol), 1-hydroxybenzotriazole (46 mg, 0.34mmol) and N,N-dimethylformamide (5.0 mL) as starting materials and inthe same manner as in Example 318, the title compound (41 mg, 26%) wasobtained as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.73-0.88 (4H, m), 1.82-1.98 (1H, m), 3.41(3H, s), 6.99-7.14 (2H, m), 7.46 (1H, t, J=8.1 Hz), 7.58-7.65 (1H, m),7.66 (1H, t, J=2.1 Hz), 7.88 (1H, d, J=4.2 Hz), 7.97 (1H, s), 8.03-8.09(2H, m), 10.66 (1H, s), 11.09 (1H, s).

Example 325 Production ofN-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-2-(1-hydroxy-1-methylethyl)-1,3-thiazole-5-carboxamide

UsingN-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(150 mg, 0.49 mmol),2-(1-hydroxy-1-methylethyl)-1,3-thiazole-5-carboxylic acid (96 mg, 0.51mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride(95 mg, 0.50 mmol), 1-hydroxybenzotriazole (67 mg, 0.50 mmol) andN,N-dimethylformamide (8.0 mL) as starting materials and in the samemanner as in Example 318, the title compound (99 mg, 43%) was obtainedas a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.73-0.85 (4H, m), 1.51 (6H, s), 1.85-1.98(1H, m), 6.17 (1H, s), 6.98-7.04 (1H, m), 7.07 (1H, d, J=9.6 Hz), 7.44(1H, t, J=8.1 Hz), 7.54-7.68 (2H, m), 7.98 (1H, s), 8.06 (1H, d, J=9.6Hz), 8.43 (1H, s), 10.42 (1H, s), 11.09 (1H, s).

Example 326 Production of3-(4-cyanotetrahydro-2H-pyran-4-yl)-N-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]benzamide

UsingN-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(150 mg, 0.49 mmol), 3-(4-cyanotetrahydro-2H-pyran-4-yl)benzoic acid(120 mg, 0.51 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimidehydrochloride (95 mg, 0.50 mmol), 1-hydroxybenzotriazole (67 mg, 0.50mmol), triethylamine (130 μL, 0.97 mmol) and N,N-dimethylformamide (8.0mL) as starting materials and in the same manner as in Example 318, thetitle compound (150 mg, 58%) was obtained as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.67-0.92 (4H, m), 1.85-1.98 (1H, m),2.10-2.23 (4H, m), 3.58-3.79 (2H, m), 3.86-4.15 (2H, m), 6.95-7.05 (1H,m), 7.08 (1H, d, J=9.6 Hz), 7.45 (1H, t, J=8.1 Hz), 7.52-7.70 (2H, m),7.71 (1H, t, J=2.1 Hz), 7.76-7.85 (1H, m), 7.92-8.00 (2H, m), 8.02-8.12(2H, m), 10.44 (1H, s), 11.09 (1H, s).

Example 327 Production ofN-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-2-(trifluoromethyl)pyrimidine-4-carboxamide

UsingN-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(150 mg, 0.49 mmol), 2-(trifluoromethyl)pyrimidine-4-carboxylic acid(150 mg, 0.83 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimidehydrochloride (100 mg, 0.53 mmol), 1-hydroxybenzotriazole (72 mg,0.53=mol) and N,N-dimethylformamide (6.0 mL) as starting materials andin the same manner as in Example 318, the title compound (130 mg, 54%)was obtained as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.73-0.88 (4H, m), 1.84-1.98 (1H, m),7.04-7.15 (2H, m), 7.49 (1H, t, J=8.1 Hz), 7.72-7.86 (2H, m), 7.98 (1H,s), 8.06 (1H, d, J=9.6 Hz), 8.36 (1H, d, J=4.8 Hz), 9.35 (1H, d, J=4.8Hz), 10.82 (1H, s), 11.09 (1H, s).

Example 328 Production ofN-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-5-(ethylsulfonyl)thiophene-2-carboxamide

UsingN-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(150 mg, 0.49 mmol), 5-(ethylsulfonyl)thiophene-2-carboxylic acid (110mg, 0.50 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimidehydrochloride (98 mg, 0.51 mmol), 1-hydroxybenzotriazole (69 mg, 0.51mmol) and N,N-dimethylformamide (6.0 mL) as starting materials and inthe same manner as in Example 318, the title compound (180 mg, 71%) wasobtained as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.76-0.86 (4H, m), 1.19 (3H, t, J=7.2 Hz),1.86-1.98 (1H, m), 3.47 (2H, q, J=7.2 Hz), 7.01-7.12 (2H, m), 7.46 (1H,t, J=8.1 Hz), 7.58-7.64 (1H, m), 7.66 (1H, t, J=2.1 Hz), 7.86 (1H, d,J=3.9 Hz), 7.97 (1H, s), 8.06 (1H, d, J=9.6 Hz), 8.09 (1H, d, J=3.9 Hz),10.66 (1H, s), 11.09 (1H, s).

Example 329 Production of5-acetyl-N-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]thiophene-2-carboxamide

UsingN-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(150 mg, 0.49 mmol), 5-acetylthiophene-2-carboxylic acid (85 mg, 0.50mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride(98 mg, 0.51 mmol), 1-hydroxybenzotriazole (69 mg, 0.51 mmol) andN,N-dimethylformamide (6.0 mL) as starting materials and in the samemanner as in Example 318, the title compound (110 mg, 48%) was obtainedas a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.75-0.85 (4H, m), 1.86-1.98 (1H, m), 2.58(3H, s), 7.00-7.13 (2H, m), 7.45 (1H, t, J=8.1 Hz), 7.59-7.66 (1H, m),7.67 (1H, t, J=2.1 Hz), 7.96-8.01 (2H, m), 8.02-8.11 (2H, m), 10.55 (1H,s), 11.09 (1H, s).

Example 330 Production of3-(1-cyano-1-methylethyl)-N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]benzamide

To a solution of 3-(1-cyano-1-methylethyl)benzoic acid (560 mg, 2.97mmol) in tetrahydrofuran (15 mL) were added oxalyl chloride (320 μL,3.71 mmol) and N,N-dimethylformamide (2 drops), and the mixture wasstirred at room temperature for 1 hr. The solvent was evaporated underreduced pressure, and the residue was dissolved in N-methylpyrrolidone(15 mL).N-[6-(3-Amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(800 mg, 2.47 mmol) was added to the mixture, and the mixture wasstirred at room temperature for 12 hr. The reaction mixture was dilutedwith 1N hydrochloric acid, and the mixture was extracted with ethylacetate. The organic layer was washed with 5% aqueous sodiumhydrogencarbonate solution and saturated brine, dried over anhydroussodium sulfate, and filtrated. The solvent was evaporated under reducedpressure, and the residue was purified by NH silica gel columnchromatography (ethyl acetate/hexane=50/50→100/0) to give a colorlessoil. The oil was dissolved ethyl acetate, and diisopropyl ether wasadded to allow precipitation to give the title compound (220 mg, 18%) asa white solid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.71-0.86 (4H, m), 1.74 (6H, s), 1.84-1.98(1H, m), 2.27 (3H, s), 7.05 (1H, d, J=9.6 Hz), 7.10 (1H, dd, J=8.4, 2.7Hz), 7.31 (1H, d, J=2.7 Hz), 7.36 (1H, d, J=8.4 Hz), 7.59 (1H, t, J=7.8Hz), 7.70-7.80 (1H, m), 7.91-7.99 (2H, m), 8.00-8.11 (2H, m), 10.04 (1H,s), 11.07 (1H, s).

Example 331 Production ofN-{6-[(5-bromopyridin-3-yl)oxy]imidazo[1,2-b]pyridazin-2-yl}cyclopropanecarboxamide

To a solution ofN-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (1.7 g,5.0 mmol) in N,N-dimethylformamide (20 mL) were added5-bromopyridine-3-ol (1.7 g, 10 mmol) and potassium carbonate (1.7 g, 13mmol), and the mixture was stirred at 140° C. for 8 hr. After coolingthe mixture to room temperature, the mixture was diluted with water, andextracted with ethyl acetate. The organic layer was washed with 5%aqueous sodium hydrogencarbonate solution and saturated brine, driedover anhydrous sodium sulfate, and filtrated. The solvent was evaporatedunder reduced pressure, and the residue was purified by silica gelcolumn chromatography (ethyl acetate/hexane=50/50→100/0), andprecipitated from ethyl acetate/diisopropyl ether to give the titlecompound (1.6 g, 85%) as a yellow powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.67-0.90 (4H, m), 1.85-1.98 (1H, m), 7.16(1H, m), 7.98 (1H, s), 8.08 (1H, d, J=9.6 Hz), 8.19-8.25 (1H, m),8.61-8.67 (2H, m), 11.09 (1H, s).

Example 332 Production ofN-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)pyridin-3-yl]-3-(trifluoromethyl)benzamide

To a solution ofN-{6-[(5-bromopyridin-3-yl)oxy]imidazo[1,2-b]pyridazin-2-yl}cyclopropanecarboxamide(200 mg, 0.53 mmol), 3-(trifluoromethyl)benzamide (160 mg, 0.91 mmol),trans-1,2-diaminocyclohexane (15 mg, 0.13 mmol) and potassium carbonate(220 mg, 1.6 mmol) in 1,4-dioxane (3.0 mL) was added copper (I) iodide(25 mg, 0.13 mmol) under argon atmosphere, and the mixture was stirredat 110° C. for 60 hr. The reaction mixture was cooled, and diluted with20% tetrahydrofuran/ethyl acetate. The mixture was washed with water, 5%aqueous sodium hydrogencarbonate solution and saturated brine, driedover anhydrous magnesium sulfate, and filtrated. The solvent wasevaporated under reduced pressure, and the residue was purified by NHsilica gel column chromatography (ethyl acetate/hexane=60/40→100/0) andprecipitated from ethyl acetate/hexane to give the title compound (110mg, 42%) as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.72-0.86 (4H, m), 1.84-1.98 (1H, m), 7.17(1H, d, J=9.6 Hz), 7.81 (1H, t, J=7.8 Hz), 7.96-8.04 (2H, m), 8.10 (1H,d, J=9.6 Hz), 8.20 (1H, t, J=2.4 Hz), 8.23-8.35 (2H, m), 8.38 (1H, d,J=2.4 Hz), 8.85 (1H, d, J=2.4 Hz), 10.83 (1H, s), 11.10 (1H, s).

Example 333 Production of methyl3-({[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]amino}carbonyl)benzoate

UsingN-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(250 mg, 0.81 mmol), 3-(methoxycarbonyl)benzoic acid (150 mg, 0.83mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride(160 mg, 0.84 mmol), 1-hydroxybenzotriazole (110 mg, 0.81 mmol) andN,N-dimethylformamide (8.0 mL) as starting materials and in the samemanner as in Example 318, the title compound (270 mg, 72%) was obtainedas a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.74-0.85 (4H, m), 1.84-1.98 (1H, m), 3.91(3H, s), 6.97-7.05 (1H, m), 7.08 (1H, d, J=9.6 Hz), 7.45 (1H, t, J=8.1Hz), 7.63-7.79 (3H, m), 7.98 (1H, s), 8.06 (1H, d, J=9.6 Hz), 8.12-8.19(1H, m), 8.19-8.26 (1H, m), 8.52 (1H, t, J=1.5 Hz), 10.59 (1H, s), 11.09(1H, s).

Example 334 Production ofN-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-3-(1-hydroxy-1-methylethyl)benzamide

To a solution of methyl3-({[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]amino}carbonyl)benzoatein tetrahydrofuran (5.0 mL) was added dropwise a solution of 1.4M methylmagnesium bromide in tetrahydrofuran/toluene (0.76 mL, 1.1 mmol) underice-cooling. After dropwise addition, the reaction mixture was stirredat room temperature for 12 hr, and water (10 mL) was added. 1NHydrochloric acid (5.0 mL) was added to the mixture, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, dried over anhydrous sodium sulfate, and filtrated. Thesolvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography (ethylacetate/hexane=40/60→100/0) and precipitated from diisopropylether/hexane to give the title compound (19 mg, 19%) as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.75-0.85 (4H, m), 1.46 (6H, s), 1.85-1.97(1H, m), 5.14 (1H, s), 6.96-7.03 (1H, m), 7.07 (1H, d, J=9.6 Hz),7.37-7.50 (2H, m), 7.67 (2H, m), 7.73 (1H, t, J=2.1 Hz), 7.75-7.81 (1H,m), 7.98 (1H, s), 8.01 (1H, t, J=1.5 Hz), 8.05 (1H, d, J=9.6 Hz), 10.35(1H, s), 11.09 (1H, s).

Example 335 Production of3-(1-cyano-1-methylethyl)-N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]benzamide

To a solution of 3-(1-cyano-1-methylethyl)benzoic acid (100 mg, 0.55mmol) in tetrahydrofuran (2.0 mL) were added oxalyl chloride (59 μL,0.69 mmol) and N,N-dimethylformamide (1 drop), and the mixture wasstirred at room temperature for 2 hr. The solvent was evaporated underreduced pressure, and the residue was dissolved in N-methylpyrrolidone(2 mL).N-[6-(3-Amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(150 mg, 0.46 mmol) was added to the mixture, and the mixture wasstirred at room temperature for 10 hr. The reaction mixture was dilutedwith 1N aqueous sodium hydroxide solution. The mixture was extractedwith ethyl acetate, and the organic layer was washed with 5% aqueoussodium hydrogencarbonate solution and saturated brine, dried overanhydrous sodium sulfate, and filtrated. The solvent was evaporatedunder reduced pressure, and the residue was purified by NH silica gelcolumn chromatography (ethyl acetate/hexane=40/60→100/0), andprecipitated from ethyl acetate/diisopropyl ether to give the titlecompound (140 mg, 62%) as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.74-0.85 (4H, m), 1.74 (6H, s), 1.85-1.98(1H, m), 7.08 (1H, d, J=9.6 Hz), 7.15-7.26 (1H, m), 7.34-7.48 (1H, m),7.52-7.65 (2H, m), 7.71-7.82 (1H, m), 7.89-7.98 (2H, m), 8.01-8.12 (2H,m), 10.32 (1H, s), 11.07 (1H, s).

Example 336 Production ofN-[4-chloro-5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-3-(1-cyano-1-methylethyl)benzamide

Using 3-(1-cyano-1-methylethyl)benzoic acid (100 mg, 0.55 mmol), oxalylchloride (59 μL, 0.69 mmol), N,N-dimethylformamide (1 drop),tetrahydrofuran (2.0 mL),N-[6-(5-amino-2-chloro-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(170 mg, 0.46 mmol) and N-methylpyrrolidone (2.0 mL) as startingmaterials and in the same manner as in Example 335, the title compound(170 mg, 70%) was obtained as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.66-0.91 (4H, m), 1.74 (6H, s), 1.86-1.98(1H, m), 7.18 (1H, d, J=9.6 Hz), 7.60 (1H, t, J=7.8 Hz), 7.71-7.86 (3H,m), 7.89-7.99 (2H, m), 8.04-8.16 (2H, m), 10.42 (1H, s), 11.08 (1H, s).

Example 337 Production of3-(1-cyano-1-methylethyl)-N-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-4-methylphenyl]benzamide

UsingN-[6-(5-amino-2-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(150 mg, 0.46 mmol), 3-(1-cyano-1-methylethyl)benzoic acid (92 mg, 0.49mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride(94 mg, 0.49 mmol), 1-hydroxybenzotriazole (66 mg, 0.49 mmol) andN,N-dimethylformamide (7.0 mL) as starting materials and in the samemanner as in Example 318, the title compound (160 mg, 70%) was obtainedas a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.75-0.84 (4H, m), 1.73 (6H, s), 1.85-1.98(1H, m), 2.15 (3H, s), 7.08 (1H, d, J=9.6 Hz), 7.34 (1H, d, J=8.4 Hz),7.54-7.66 (3H, m), 7.70-7.78 (1H, m), 7.86-7.96 (2H, m), 8.01 (1H, t,J=1.8 Hz), 8.05 (1H, d, J=9.6 Hz), 10.37 (1H, s), 11.07 (1H, s).

Example 338 Production ofN-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-4-methylphenyl]-3-(trifluoromethyl)benzamide

UsingN-[6-(5-amino-2-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(150 mg, 0.46 mmol), 3-(trifluoromethyl)benzoic acid (93 mg, 0.49 mmol),N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (94 mg,0.49 mmol), 1-hydroxybenzotriazole (66 mg, 0.49 mmol) andN,N-dimethylformamide (7.0 mL) as starting materials and in the samemanner as in Example 318, the title compound (166 mg, 72%) was obtainedas a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.73-0.89 (4H, m), 1.82-2.02 (1H, m), 2.16(3H, s), 7.08 (1H, d, J=9.6 Hz), 7.35 (1H, d, J=8.4 Hz), 7.55-7.69 (2H,m), 7.77 (1H, t, J=7.8 Hz), 7.91-8.00 (2H, m), 8.06 (1H, d, J=9.6 Hz),8.19-8.31 (2H, m), 10.51 (1H, s), 11.07 (1H, s).

Example 339 Production of3-(1-cyanocyclopropyl)-N-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]benzamide

UsingN-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(170 mg, 0.55 mmol), 3-(1-cyanocyclopropyl)benzoic acid (100 mg, 0.55mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride(110 mg, 0.55 mmol), 1-hydroxybenzotriazole (74 mg, 0.55 mmol) andN,N-dimethylformamide (10 mL) as starting materials and in the samemanner as in Example 318, the title compound (122 mg, 47%) was obtainedas a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.58-0.92 (4H, m), 1.55-1.68 (2H, m),1.77-1.86 (2H, m), 1.86-1.99 (1H, m), 7.00 (1H, m), 7.07 (1H, d, J=9.6Hz), 7.44 (1H, t, J=8.1 Hz), 7.50-7.61 (2H, m), 7.61-7.68 (1H, m), 7.71(1H, t, J=2.1 Hz), 7.81 (1H, s), 7.84-7.91 (1H, m), 7.98 (1H, s), 8.06(1H, d, J=9.6 Hz), 10.42 (1H, s), 11.09 (1H, s).

Example 340 Production ofN-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-3,5-bis(trifluoromethyl)benzamide

Using 3,5-bis(trifluoromethyl)benzoic acid (120 mg, 0.45 mmol), oxalylchloride (48 μL, 0.56 mmol), N,N-dimethylformamide (1 drop),tetrahydrofuran (2.0 mL),N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(120 mg, 0.37 mmol) and N-methylpyrrolidone (2.0 mL) as startingmaterials and in the same manner as in Example 335, the title compound(63 mg, 31%) was obtained as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.73-0.86 (4H, m), 1.85-1.98 (1H, m),7.01-7.15 (2H, m), 7.48 (1H, t, J=8.1 Hz), 7.63-7.69 (1H, m), 7.71 (1H,t, J=2.1 Hz), 7.98 (1H, s), 8.06 (1H, d, J=9.6 Hz), 8.38 (1H, s), 8.59(2H, s), 10.77 (1H, s), 11.09 (1H, s).

Example 341 Production ofN-(3-{[2-(acetylamino)imidazo[1,2-b]pyridazin-6-yl]oxy}phenyl)-3-(1-cyano-1-methylethyl)benzamide

Using 3-(1-cyano-1-methylethyl)benzoic acid (160 mg, 0.85 mmol), oxalylchloride (90 μL, 1.1 mmol), N,N-dimethylformamide (1 drop),tetrahydrofuran (4.0 mL),N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]acetamide (200 mg,0.71 mmol) and N-methylpyrrolidone (5.0 mL) as starting materials and inthe same manner as in Example 335, the title compound (220 mg, 69%) wasobtained as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.74 (6H, s), 2.07 (3H, s), 6.97-7.05 (1H,m), 7.08 (1H, d, J=9.6 Hz), 7.45 (1H, t, J=8.1 Hz), 7.60 (1H, t, J=7.8Hz), 7.63-7.69 (1H, m), 7.70-7.80 (2H, m), 7.88-7.96 (1H, m), 8.00 (1H,s), 8.02 (1H, t, J=1.8 Hz), 8.05 (1H, d, J=9.6 Hz), 10.45 (1H, s), 10.80(1H, s).

Example 342 Production of3-(1-cyanocyclohexyl)-N-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]benzamide

Using 3-(1-cyanocyclohexyl)benzoic acid (100 mg, 0.45 mmol), oxalylchloride (48 μL, 0.56 mmol), N,N-dimethylformamide (1 drop),tetrahydrofuran (3.0 mL),N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(120 mg, 0.37 mmol) and N-methylpyrrolidone (2.0 mL) as startingmaterials and in the same manner as in Example 335, the title compound(150 mg, 78%) was obtained as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.74-0.85 (4H, m), 1.22-1.41 (1H, m),1.54-1.98 (8H, m), 2.05-2.20 (2H, m), 6.97-7.05 (1H, m), 7.08 (1H, d,J=9.6 Hz), 7.45 (1H, t, J=8.1 Hz), 7.60 (1H, t, J=7.8 Hz), 7.63-7.69(1H, m), 7.72 (1H, t, J=2.1 Hz), 7.74-7.80 (1H, m), 7.89-7.96 (1H, m),7.98 (1H, s), 8.01-8.10 (2H, m), 10.44 (1H, s), 11.09 (1H, s).

Example 343 Production of3-(1-cyano-1-methylethyl)-N-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-4-methoxyphenyl]benzamide

UsingN-[6-(5-amino-2-methoxyphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(150 mg, 0.44 mmol), 3-(1-cyano-1-methylethyl)benzoic acid (88 mg, 0.46mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride(87 mg, 0.46 mmol), 1-hydroxybenzotriazole (62 mg, 0.46 mmol) andN,N-dimethylformamide (10 mL) as starting materials and in the samemanner as in Example 318, the title compound (160 mg, 71%) was obtainedas a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.75-0.84 (4H, m), 1.74 (6H, s), 1.85-1.97(1H, m), 3.72 (3H, s), 7.06 (1H, d, J=9.6 Hz), 7.22 (1H, d, J=9.0 Hz),7.59 (1H, t, J=7.8 Hz), 7.65 (1H, dd, J=9.0, 2.4 Hz), 7.71 (1H, d, J=2.4Hz), 7.72-7.78 (1H, m), 7.89 (1H, s), 7.90-7.95 (1H, m), 7.97-8.07 (2H,m), 10.32 (1H, s), 11.05 (1H, s).

Example 344 Production ofN-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-4-methoxyphenyl]-3-(trifluoromethyl)benzamide

To a solution ofN-[6-(5-amino-2-methoxyphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(150 mg, 0.44 mmol) in N-methylpyrrolidone (6.0 mL) was added3-(trifluoromethyl)benzoyl chloride (92 mg, 0.44 mmol) underice-cooling, and the mixture was stirred at room temperature for 12 hr.The reaction mixture was diluted with 1N hydrochloric acid and extractedwith ethyl acetate, and the organic layer was washed with 5% aqueoussodium hydrogencarbonate solution and saturated brine, dried overanhydrous sodium sulfate, and filtrated. The solvent was evaporatedunder reduced pressure, and the residue was purified by NH silica gelcolumn chromatography (ethyl acetate/hexane=50/50→100/0), andprecipitated from ethyl acetate/diisopropyl ether to give the titlecompound (180 mg, 80%) as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.74-0.83 (4H, m), 1.82-1.97 (1H, m), 3.73(3H, s), 7.06 (1H, d, J=9.6 Hz), 7.23 (1H, d, J=9.0 Hz), 7.66 (1H, dd,J=9.0, 2.4 Hz), 7.73 (1H, d, J=2.4 Hz), 7.78 (1H, t, J=7.8 Hz), 7.89(1H, s), 7.96 (1H, d, J=7.8 Hz), 8.01 (1H, d, J=10.2 Hz), 8.18-8.36 (2H,m), 10.48 (1H, s), 11.05 (1H, s).

Example 345 Production of3-(1-cyanocyclopropyl)-N-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-4-methylphenyl]benzamide

UsingN-[6-(5-amino-2-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(150 mg, 0.46 mmol), 3-(1-cyanocyclopropyl)benzoic acid (91 mg, 0.49mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride(94 mg, 0.49 mmol), 1-hydroxybenzotriazole (66 mg, 0.49 mmol) andN,N-dimethylformamide (7.0 mL) as starting materials and in the samemanner as in Example 318, the title compound (178 mg, 75%) was obtainedas a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.69-0.88 (4H, m), 1.55-1.65 (2H, m),1.76-1.84 (2H, m), 1.85-2.00 (1H, m), 2.15 (3H, s), 7.08 (1H, d, J=9.6Hz), 7.34 (1H, d, J=8.1 Hz), 7.48-7.69 (4H, m), 7.80 (1H, s), 7.82-7.89(1H, m), 7.92 (1H, s), 8.05 (1H, d, J=9.6 Hz), 10.34 (1H, s), 11.06 (1H,s).

Example 346 Production of3-(1-cyanocyclobutyl)-N-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]benzamide

Using 3-(1-cyanocyclobutyl)benzoic acid (110 mg, 0.56 mmol), oxalylchloride (60 μL, 0.70 mmol), N,N-dimethylformamide (1 drop),tetrahydrofuran (3.0 mL),N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(150 mg, 0.47 mmol) and N-methylpyrrolidone (3.0 mL) as startingmaterials and in the same manner as in Example 335, the title compound(140 mg, 60%) was obtained as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.72-0.86 (4H, m), 1.81-2.12 (2H, m),2.20-2.41 (1H, m), 2.60-2.86 (4H, m), 6.97-7.05 (1H, m), 7.07 (1H, d,J=9.6 Hz), 7.45 (1H, t, J=8.1 Hz), 7.60 (1H, t, J=7.8 Hz), 7.64-7.76(3H, m), 7.89-8.01 (3H, m), 8.06 (1H, d, J=9.6 Hz), 10.46 (1H, s), 11.09(1H, s).

Example 347 Production of3-(1-cyanocyclobutyl)-N-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-4-methylphenyl]benzamide

Using 3-(1-cyanocyclobutyl)benzoic acid (110 mg, 0.56 mmol), oxalylchloride (60 μL, 0.70 mmol), N,N-dimethylformamide (1 drop),tetrahydrofuran (3.0 mL),N-[6-(5-amino-2-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(150 mg, 0.46 mmol) and N-methylpyrrolidone (3.0 mL) as startingmaterials and in the same manner as in Example 335, the title compound(150 mg, 64%) was obtained as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.66-0.92 (4H, m), 1.72-2.11 (2H, m), 2.15(3H, s), 2.20-2.42 (1H, m), 2.60-2.94 (4H, m), 7.08 (1H, d, J=9.6 Hz),7.34 (1H, d, J=8.4 Hz), 7.53-7.75 (4H, m), 7.81-7.99 (3H, m), 8.05 (1H,d, J=9.6 Hz), 10.38 (1H, s), 11.07 (1H, s).

Example 348 Production ofN-[4-chloro-5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-3-(1-cyanocyclobutyl)benzamide

Using 3-(1-cyanocyclobutyl)benzoic acid (110 mg, 0.56 mmol), oxalylchloride (60 μL, 0.70 mmol), N,N-dimethylformamide (1 drop),tetrahydrofuran (3.0 mL),N-[6-(5-amino-2-chloro-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(170 mg, 0.46 mmol) and N-methylpyrrolidone (3.0 mL) as startingmaterials and in the same manner as in Example 335, the title compound(170 mg, 68%) was obtained as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.80 (4H, s), 1.85-1.96 (1H, m), 1.97-2.12(1H, m), 2.20-2.41 (1H, m), 2.60-2.88 (4H, m), 7.18 (1H, d, J=9.6 Hz),7.61 (1H, t, J=7.8 Hz), 7.67-7.75 (1H, m), 7.79 (1H, d, J=2.7 Hz), 7.82(1H, s), 7.88-7.97 (2H, m), 8.02 (1H, t, J=1.5 Hz), 8.09 (1H, d, J=9.6Hz), 10.44 (1H, s), 11.08 (1H, s).

Example 349 Production of2-chloro-N-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-5-(trifluoromethyl)benzamide

UsingN-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(100 mg, 0.32 mmol), 2-chloro-5-(trifluoromethyl)benzoyl acid chloride(87 mg, 0.36 mmol) and N-methylpyrrolidone (3.0 mL) as startingmaterials and in the same manner as in Example 344, the title compound(130 mg, 75%) was obtained as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.74-0.86 (4H, m), 1.86-1.98 (1H, m),6.95-7.18 (2H, m), 7.45 (1H, t, J=8.1 Hz), 7.50-7.58 (1H, m), 7.67 (1H,t, J=2.1 Hz), 7.77-7.93 (2H, m), 7.97 (1H, s), 8.02-8.08 (2H, m), 10.80(1H, s), 11.09 (1H, s).

Example 350 Production of2-chloro-N-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-3-(trifluoromethyl)benzamide

Using 2-chloro-3-(trifluoromethyl)benzoic acid (88 mg, 0.39 mmol),oxalyl chloride (42 μL, 0.49 mmol), N,N-dimethylformamide (1 drop),tetrahydrofuran (3.0 mL),N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(100 mg, 0.32 mmol) and N-methylpyrrolidone (4.0 mL) as startingmaterials and in the same manner as in Example 335, the title compound(110 mg, 68%) was obtained as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.75-0.86 (4H, m), 1.86-1.97 (1H, m),6.99-7.15 (2H, m), 7.45 (1H, t, J=8.1 Hz), 7.49-7.58 (1H, m), 7.61-7.76(2H, m), 7.88-7.95 (1H, m), 7.96-8.02 (2H, m), 8.05 (1H, d, J=9.6 Hz),10.83 (1H, s), 11.09 (1H, s).

Example 351 Production ofN-[4-chloro-5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-3-(1-cyanocyclopropyl)benzamide

Using 3-(1-cyanocyclopropyl)benzoic acid (100 mg, 0.50 mmol), oxalylchloride (55 μL, 0.62 mmol), N,N-dimethylformamide (1 drop),tetrahydrofuran (3.0 mL),N-[6-(5-amino-2-chloro-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(150 mg, 0.42 mmol) and N-methylpyrrolidone (3.0 mL) as startingmaterials and in the same manner as in Example 335, the title compound(160 mg, 73%) was obtained as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.73-0.83 (4H, m), 1.55-1.66 (2H, m),1.76-1.85 (2H, m), 1.86-1.97 (1H, m), 7.18 (1H, d, J=9.6 Hz), 7.46-7.65(2H, m), 7.79 (1H, d, J=2.7 Hz), 7.82 (1H, s), 7.83-7.91 (2H, m), 7.92(1H, s), 8.09 (1H, d, J=9.6 Hz), 10.40 (1H, s), 11.08 (1H, s).

Example 352 Production ofN-[6-(3-amino-2-chloro-6-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide

To a solution ofN-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (2.0 g,6.1 mmol) in N,N-dimethylformamide (20 mL) were added3-amino-2-chloro-6-methylphenol (1.9 g, 12 mmol) and potassium carbonate(2.1 g, 15 mmol), and the mixture was stirred at 140° C. for 12 hr.After cooling the mixture to room temperature, the mixture was dilutedwith water and extracted with ethyl acetate. The organic layer waswashed with 5% aqueous sodium hydrogencarbonate solution and saturatedbrine, dried over anhydrous sodium sulfate, and filtrated. The solventwas evaporated under reduced pressure, and the residue was purified byNH silica gel column chromatography (ethyl acetate/hexane=50/50→80/20)and precipitated from methanol/diisopropyl ether to give the titlecompound (1.4 g, 64%) as a pale-yellow powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.74-0.83 (4H, m), 1.85-1.97 (1H, m), 2.00(3H, s), 5.37 (2H, s), 6.69 (1H, d, J=8.4 Hz), 6.99 (1H, d, J=9.0 Hz),7.07 (1H, d, J=9.6 Hz), 7.87 (1H, s), 8.03 (1H, d, J=9.6 Hz), 11.04 (1H,s).

Example 353 Production ofN-[2-chloro-3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-4-methylphenyl]-3-(1-cyano-1-methylethyl)benzamide

Using 3-(1-cyanocyclopropyl)benzoic acid (95 mg, 0.50 mmol), oxalylchloride (55 μL, 0.63 mmol), N,N-dimethylformamide (1 drop),tetrahydrofuran (3.0 mL),N-[6-(3-amino-2-chloro-6-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(150 mg, 0.42 mmol) and N-methylpyrrolidone (3.0 mL) as startingmaterials and in the same manner as in Example 335, the title compound(110 mg, 51%) was obtained as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.63-0.95 (4H, m), 1.74 (6H, s), 1.82-1.97(1H, m), 2.22 (3H, s), 7.20 (1H, d, J=9.6 Hz), 7.34-7.53 (2H, m), 7.59(1H, t, J=7.8 Hz), 7.76 (1H, dq, J=7.8, 1.2 Hz), 7.85 (1H, s), 7.97 (1H,dt, J=7.8, 1.2 Hz), 8.06-8.15 (2H, m), 10.25 (1H, s), 11.06 (1H, s).

Example 354 Production ofN-[2-chloro-3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-4-methylphenyl]-3-(trifluoromethyl)benzamide

UsingN-[6-(3-amino-2-chloro-6-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(150 mg, 0.42 mmol), 3-(trifluoromethyl)benzoyl chloride (92 mg, 0.44mmol) and N-methylpyrrolidone (5.0 mL) as starting materials and in thesame manner as in Example 344, the title compound (130 mg, 60%) wasobtained as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.70-0.87 (4H, m), 1.81-1.98 (1H, m), 2.22(3H, s), 7.20 (1H, d, J=9.6 Hz), 7.33-7.58 (2H, m), 7.79 (1H, t, J=7.8Hz), 7.85 (1H, s), 7.98 (1H, d, J=7.8 Hz), 8.09 (1H, d, J=9.6 Hz), 8.29(1H, d, J=7.8 Hz), 8.34 (1H, s), 10.45 (1H, s), 11.06 (1H, s).

Example 355 Production of3-(1-cyanocyclopropyl)-N-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-4-methoxyphenyl]benzamide

Using 3-(1-cyanocyclopropyl)benzoic acid (40 mg, 0.21 mmol), oxalylchloride (23 μL, 0.27 mmol), N,N-dimethylformamide (1 drop),tetrahydrofuran (2.0 mL),N-[6-(5-amino-2-methoxyphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(60 mg, 0.18 mmol) and N-methylpyrrolidone (2.0 mL) as startingmaterials and in the same manner as in Example 335, the title compound(67 mg, 74%) was obtained as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.70-0.83 (4H, m), 1.54-1.65 (2H, m),1.75-1.86 (2H, m), 1.86-1.98 (1H, m), 3.72 (3H, s), 7.06 (1H, d, J=9.6Hz), 7.22 (1H, d, J=9.0 Hz), 7.48-7.60 (2H, m), 7.64 (1H, dd, J=9.0, 2.4Hz), 7.71 (1H, d, J=2.4 Hz), 7.82 (1H, s), 7.84-7.92 (2H, m), 8.01 (1H,d, J=9.6 Hz), 10.31 (1H, s), 11.06 (1H, s).

Example 356 Production of3-(1-cyanocyclobutyl)-N-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-4-methoxyphenyl]benzamide

Using 3-(1-cyanocyclobutyl)benzoic acid (43 mg, 0.21 mmol), oxalylchloride (23 μL, 0.27 mmol), N,N-dimethylformamide (1 drop),tetrahydrofuran (2.0 mL),N-[6-(5-amino-2-methoxyphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(60 mg, 0.18 mmol) and N-methylpyrrolidone (2.0 mL) as startingmaterials and in the same manner as in Example 335, the title compound(68 mg, 74%) was obtained as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.72-0.86 (4H, m), 1.86-1.96 (1H, m),2.21-2.38 (2H, m), 2.64-2.87 (4H, m), 3.72 (3H, s), 7.06 (1H, d, J=9.6Hz), 7.22 (1H, d, J=9.0 Hz), 7.53-7.75 (4H, m), 7.89 (1H, s), 7.90-8.07(3H, m), 10.35 (1H, s), 11.06 (1H, s).

Example 357 Production ofN-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-3-(2-oxopyrrolidin-1-yl)benzamide

Using 3-(2-oxopyrrolidin-1-yl)benzoic acid (120 mg, 0.58 mmol), oxalylchloride (60 μL, 0.68 mmol), N,N-dimethylformamide (1 drop),tetrahydrofuran (3.0 mL),N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(150 mg, 0.49 mmol) and N-methylpyrrolidone (2.0 mL) as startingmaterials and in the same manner as in Example 335, the title compound(170 mg, 70%) was obtained as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.75-0.86 (4H, m), 1.85-1.97 (1H, m),2.01-2.16 (2H, m), 2.52-2.56 (2H, m), 3.90 (2H, t, J=6.6 Hz), 6.97-7.03(1H, m), 7.07 (1H, d, J=9.6 Hz), 7.44 (1H, t, J=8.1 Hz), 7.52 (1H, t,J=8.1 Hz), 7.61-7.75 (3H, m), 7.89-7.95 (1H, m), 7.98 (1H, s), 8.02-8.11(2H, m), 10.40 (1H, s), 11.09 (1H, s).

Example 358 Production ofN-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-3-(trifluoromethoxy)benzamide

Using 3-(trifluoromethoxy)benzoic acid (120 mg, 0.58 mmol), oxalylchloride (60 μL, 0.68 mmol), N,N-dimethylformamide (1 drop),tetrahydrofuran (3.0 mL),N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(150 mg, 0.49 mmol) and N-methylpyrrolidone (2.0 mL) as startingmaterials and in the same manner as in Example 335, the title compound(130 mg, 54%) was obtained as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.73-0.87 (4H, m), 1.83-1.98 (1H, m),6.99-7.05 (1H, m), 7.08 (1H, d, J=9.6 Hz), 7.45 (1H, t, J=8.1 Hz),7.58-7.70 (3H, m), 7.72 (1H, t, J=2.1 Hz), 7.89 (1H, s), 7.95-8.03 (2H,m), 8.06 (1H, d, J=9.6 Hz), 10.51 (1H, s) 11.09 (1H, s).

Example 359 Production ofN-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-4-methoxyphenyl]-3-(trifluoromethoxy)benzamide

Using 3-(trifluoromethoxy)benzoic acid (120 mg, 0.58 mmol), oxalylchloride (60 μL, 0.68 mmol), N,N-dimethylformamide (1 drop),tetrahydrofuran (3.0 mL),N-[6-(5-amino-2-methoxyphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(150 mg, 0.49 mmol) and N-methylpyrrolidone (2.0 mL) as startingmaterials and in the same manner as in Example 335, the title compound(130 mg, 54%) was obtained as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.72-0.86 (4H, m), 1.83-1.98 (1H, m), 3.72(3H, s), 7.06 (1H, d, J=9.6 Hz), 7.22 (1H, d, J=9.1 Hz), 7.54-7.78 (4H,m), 7.84-7.93 (2H, m), 7.96-8.08 (2H, m), 10.40 (1H, s), 11.05 (1H, s).

Example 360 Production of3-(1-cyanoethyl)-N-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-4-methoxyphenyl]benzamide

Using 3-(1-cyanoethyl)benzoic acid (62 mg, 0.35 mmol), oxalyl chloride(38 μL, 0.44 mmol), N,N-dimethylformamide (1 drop), tetrahydrofuran (3.0mL),N-[6-(5-amino-2-methoxyphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(100 mg, 0.30 mmol) and N-methylpyrrolidone (2.0 mL) as startingmaterials and in the same manner as in Example 335, the title compound(84 mg, 58%) was obtained as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.70-0.88 (4H, m), 1.60 (3H, d, J=7.2 Hz),1.81-1.99 (1H, m), 3.72 (3H, s), 4.42 (1H, q, J=7.2 Hz), 7.06 (1H, d,J=9.6 Hz), 7.22 (1H, d, J=9.0 Hz), 7.47-7.70 (3H, m), 7.72 (1H, d, J=2.4Hz), 7.84-7.97 (3H, m), 8.01 (1H, d, J=9.9 Hz), 10.32 (1H, s), 11.05(1H, s).

Example 361 Production ofN-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-3-methoxybenzamide

Using 3-methoxybenzoic acid (48 mg, 0.32 mmol), oxalyl chloride (32 μL,0.37 mmol), N,N-dimethylformamide (1 drop), tetrahydrofuran (2.0 mL),N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(80 mg, 0.26 mmol) and N-methylpyrrolidone (2.0 mL) as startingmaterials and in the same manner as in Example 335, the title compound(49 mg, 43%) was obtained as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.77-0.85 (4H, m), 1.85-1.99 (1H, m), 3.83(3H, s), 6.95-7.03 (1H, m), 7.07 (1H, d, J=9.6 Hz), 7.12-7.21 (1H, m),7.37-7.49 (3H, m), 7.48-7.56 (1H, m), 7.61-7.70 (1H, m), 7.73 (1H, t,J=2.1 Hz), 7.98 (1H, s), 8.05 (1H, d, J=9.6 Hz), 10.34 (1H, s), 11.09(1H, s).

Example 362 Production ofN-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-3-isopropoxybenzamide

Using 3-(isopropoxy)benzoic acid (56 mg, 0.31 mmol), oxalyl chloride (33μL, 0.39 mmol), N,N-dimethylformamide (1 drop), tetrahydrofuran (3.0mL),N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(80 mg, 0.26 mmol) and N,N-dimethylacetamide (2.0 mL) as startingmaterials and in the same manner as in Example 335, the title compound(82 mg, 67%) was obtained as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.77-0.85 (4H, m), 1.29 (6H, d, J=6.0 Hz),1.85-1.98 (1H, m), 4.60-4.78 (1H, m), 6.96-7.02 (1H, m), 7.07 (1H, d,J=9.6 Hz), 7.11-7.17 (1H, m), 7.33-7.55 (4H, m), 7.63-7.71 (1H, m), 7.74(1H, t, J=2.1 Hz), 7.98 (1H, s), 8.05 (1H, d, J=9.6 Hz), 10.31 (1H, s),11.09 (1H, s).

Example 363 Production ofN-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-3-(1,1,2,2-tetrafluoroethoxy)benzamide

Using 3-(1,1,2,2-tetrafluoroethoxy)benzoic acid (74 mg, 0.31 mmol),oxalyl chloride (33 μL, 0.39 mmol), N,N-dimethylformamide (1 drop),tetrahydrofuran (3.0 mL),N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(80 mg, 0.26 mmol) and N-methylpyrrolidone (2.0 mL) as startingmaterials and in the same manner as in Example 335, the title compound(46 mg, 34%) was obtained as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.73-0.87 (4H, m), 1.85-1.99 (1H, m),6.62-7.05 (2H, m), 7.07 (1H, d, J=9.6 Hz), 7.45 (1H, t, J=8.1 Hz),7.49-7.58 (1H, m), 7.61-7.69 (2H, m), 7.72 (1H, t, J=2.1 Hz), 7.82 (1H,br. s.), 7.93-8.00 (2H, m), 8.06 (1H, d, J=9.6 Hz), 10.50 (1H, s), 11.09(1H, s).

Example 364 Production ofN-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-4-methoxyphenyl]-3-(1,1,2,2-tetrafluoroethoxy)benzamide

Using 3-(1,1,2,2-tetrafluoroethoxy)benzoic acid (85 mg, 0.35 mmol),oxalyl chloride (38 μL, 0.44=mol), N,N-dimethylformamide (1 drop),tetrahydrofuran (3.0 mL),N-[6-(5-amino-2-methoxyphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(100 mg, 0.30 mmol) and N-methylpyrrolidone (2.0 mL) as startingmaterials and in the same manner as in Example 335, the title compound(110 mg, 64%) was obtained as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.76-0.86 (4H, m), 1.84-1.98 (1H, m), 3.83(3H, s), 6.96-7.03 (1H, m), 7.07 (1H, d, J=9.6 Hz), 7.12-7.20 (1H, m),7.36-7.49 (3H, m), 7.49-7.55 (1H, m), 7.62-7.70 (1H, m), 7.73 (1H, t,J=2.1 Hz), 7.98 (1H, s), 8.05 (1H, d, J=9.6 Hz), 10.34 (1H, s), 11.09(1H, s).

Example 365 Production of3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-N-[3-(trifluoromethyl)phenyl]benzamide

Using3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)benzoicacid (100 mg, 0.30 mmol), oxalyl chloride (100 μL, 1.2 mmol),N,N-dimethylformamide (1 drop), tetrahydrofuran (2.0 mL),3-(trifluoromethyl)aniline (80 mg, 0.48 mmol) and N-methylpyrrolidone(1.0 mL) as starting materials and in the same manner as in Example 335,the title compound (13 mg, 8.9%) was obtained as a pale-yellow powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.74-0.83 (4H, m), 1.86-1.97 (1H, m), 7.12(1H, d, J=9.6 Hz), 7.46 (1H, d, J=7.8 Hz), 7.51-7.70 (3H, m), 7.83-7.99(3H, m), 8.01-8.11 (2H, m), 8.23 (1H, s), 10.59 (1H, s), 11.08 (1H, s).

Example 366 Production of3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-N-[4-(trifluoromethyl)phenyl]benzamide

Using3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)benzoicacid (30 mg, 0.089 mmol), 4-(trifluoromethyl)aniline (44 mg, 0.27 mmol),N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (26 mg,0.14 mmol), 4-(dimethylamino)pyridine (17 mg, 0.14 mmol) and pyridine(1.0 mL) as starting materials and in the same manner as in Example 318,the title compound (18 mg, 42%) was obtained as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.71-0.86 (4H, m), 1.84-1.98 (1H, m), 7.11(1H, d, J=9.6 Hz), 7.50-7.59 (1H, m), 7.65 (1H, t, J=7.9 Hz), 7.73 (2H,d, J=8.7 Hz), 7.81-7.93 (2H, m), 7.95 (1H, s), 8.00 (2H, d, J=8.7 Hz),8.07 (1H, d, J=9.6 Hz), 10.63 (1H, s), 11.08 (1H, s).

Example 367 Production of3-tert-butoxy-N-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]benzamide

Using 3-tert-butoxybenzoic acid (110 mg, 0.58 mmol), oxalyl chloride (63μL, 0.73 mmol), N,N-dimethylformamide (1 drop), tetrahydrofuran (4.0mL),N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(150 mg, 0.49 mmol) and N-methylpyrrolidone (4.0 mL) as startingmaterials and in the same manner as in Example 335, the title compound(160 mg, 57%) was obtained as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.74-0.87 (4H, m), 1.33 (9H, s), 1.85-1.98(1H, m), 6.90-7.03 (1H, m), 7.07 (1H, d, J=9.6 Hz), 7.16-7.27 (1H, m),7.36-7.48 (2H, m), 7.48-7.53 (1H, m), 7.61-7.70 (2H, m), 7.73 (1H, t,J=2.1 Hz), 7.98 (1H, s), 8.05 (1H, d, J=9.6 Hz), 10.34 (1H, s), 11.09(1H, s).

Example 368 Production ofN-(4-tert-butylphenyl)-3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)benzamide

Using3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)benzoicacid (100 mg, 0.30 mmol), 4-tert-butylaniline (57 mg, 0.36 mmol),N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (68 mg,0.36 mmol), 4-(dimethylamino)pyridine (43 mg, 0.36 mmol) and pyridine(5.0 mL) as starting materials and in the same manner as in Example 318,the title compound (70 mg, 50%) was obtained as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.68-0.88 (4H, m), 1.28 (9H, s), 1.85-1.98(1H, m), 7.11 (1H, d, J=9.6 Hz), 7.37 (2H, d, J=8.7 Hz), 7.47-7.55 (1H,m), 7.56-7.72 (3H, m), 7.77-7.92 (2H, m), 7.96 (1H, s), 8.07 (1H, d,J=9.6 Hz), 10.23 (1H, s), 11.08 (1H, s).

Example 369 Production ofN-[3-(1-cyano-1-methylethyl)phenyl]-3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)benzamide

Using3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)benzoicacid (100 mg, 0.30 mmol), 2-(3-aminophenyl)-2-methylpropanenitrile (57mg, 0.36 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimidehydrochloride (68 mg, 0.36 mmol), 4-(dimethylamino)pyridine (43 mg, 0.36mmol) and pyridine (5.0 mL) as starting materials and in the same manneras in Example 318, the title compound (64 mg, 45%) was obtained as awhite powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.68-0.89 (4H, m), 1.69 (6H, s), 1.85-1.98(1H, m), 7.11 (1H, d, J=9.6 Hz), 7.20-7.30 (1H, m), 7.41 (1H, t, J=8.0Hz), 7.48-7.57 (1H, m), 7.64 (1H, t, J=7.9 Hz), 7.74-8.00 (5H, m), 8.07(1H, d, J=9.6 Hz), 10.42 (1H, s), 11.08 (1H, s).

Example 370 Production ofN-[4-(1-cyano-1-methylethyl)phenyl]-3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)benzamide

Using3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)benzoicacid (100 mg, 0.30 mmol), 2-(4-aminophenyl)-2-methylpropanenitrile (57mg, 0.36 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimidehydrochloride (63 mg, 0.33=mol), 4-(dimethylamino)pyridine (54 mg, 0.44mmol) and pyridine (3.0 mL) as starting materials and in the same manneras in Example 318, the title compound (81 mg, 57%) was obtained as awhite powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.71-0.87 (4H, m), 1.68 (6H, s), 1.85-1.98(1H, m), 7.11 (1H, d, J=9.6 Hz), 7.45-7.56 (3H, m), 7.63 (1H, t, J=7.9Hz), 7.77-7.86 (3H, m), 7.86-7.92 (1H, m), 7.95 (1H, s), 8.07 (1H, d,J=9.4 Hz), 10.38 (1H, s), 11.08 (1H, s).

Example 371 Production of3-(1-cyano-2-cyclopropyl-1-methylethyl)-N-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-4-methoxyphenyl]benzamide

Using 3-(1-cyano-2-cyclopropyl-1-methylethyl)benzoic acid (70 mg, 0.31mmol), oxalyl chloride (33 μL, 0.38 mmol), N,N-dimethylformamide (1drop), tetrahydrofuran (2.0 mL),N-[6-(5-amino-2-methoxyphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(86 mg, 0.25 mmol) and N-methylpyrrolidone (2.0 mL) as startingmaterials and in the same manner as in Example 335, the title compound(67 mg, 48%) was obtained as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ −0.03-0.08 (1H, m), 0.16-0.27 (1H, m),0.30-0.52 (2H, m), 0.55-0.69 (1H, m), 0.73-0.86 (4H, m, J=4.5 Hz),1.69-2.12 (6H, m), 3.72 (3H, s), 7.06 (1H, d, J=9.3 Hz), 7.22 (1H, d,J=9.3 Hz), 7.59 (1H, t, J=7.8 Hz), 7.65 (1H, dd, J=8.7, 2.4 Hz),7.69-7.80 (2H, m), 7.86-7.97 (2H, m), 7.96-8.07 (2H, m), 10.31 (1H, s),11.05 (1H, s).

Example 372 Production of2-(1-cyano-1-methylethyl)-N-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-4-methoxyphenyl]-1,3-thiazole-4-carboxamide

Using 2-(1-cyano-1-methylethyl)-1,3-thiazole-4-carboxylic acid (104 mg,0.53 mmol), oxalyl chloride (57 μL, 0.66 mmol), N,N-dimethylformamide (1drop), tetrahydrofuran (5.0 mL),N-[6-(5-amino-2-methoxyphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(150 mg, 0.44 mmol) and N,N-dimethylacetamide (4.0 mL) as startingmaterials and in the same manner as in Example 335, the title compound(179 mg, 78%) was obtained as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.70-0.89 (4H, m), 1.82-1.98 (7H, m), 3.73(3H, s), 7.06 (1H, d, J=9.6 Hz), 7.22 (1H, d, J=9.4 Hz), 7.64-7.80 (2H,m), 7.89 (1H, s), 8.01 (1H, d, J=10.2 Hz), 8.47 (1H, s), 10.13 (1H, s),11.05 (1H, s).

Example 373N-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}cyclopropanecarboxamide

A mixture ofN-{3-[(2-acetamidoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}cyclopropanecarboxamide(465 mg, 1.32 mmol), 4N hydrochloric acid-ethyl acetate solution (10 mL)and methanol (10 mL) was stirred at room temperature for 14 hr. Thereaction mixture was neutralized by the addition of 8N aqueous sodiumhydroxide solution, and the mixture was extracted with ethyl acetate.The extract was washed with saturated brine, dried over anhydrousmagnesium sulfate, and filtrated. The solvent was evaporated underreduced pressure, and the residue was washed with ethylacetate/diisopropyl ether to give the title compound (376 mg, 92%) as apale-green powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.75-0.81 (4H, m), 1.69-1.79 (1H, m), 5.33(2H, s), 6.76 (1H, d, J=9.3 Hz), 6.80-6.86 (1H, m), 7.14 (1H, s),7.28-7.39 (2H, m), 7.47 (1H, t, J=1.9 Hz), 7.71 (1H, d, J=9.3 Hz), 10.30(1H, s).

Example 374 Production ofN-[6-(5-amino-2-bromophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide

To a solution ofN-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (2.2 g,6.7 mmol) in N,N-dimethylformamide (60 mL) were added5-amino-2-bromophenol (1.9 g, 10 mmol) and potassium carbonate (1.8 g,13 mmol), and the mixture was stirred at 140° C. for 12 hr. Aftercooling the mixture to room temperature, the mixture was diluted withwater, and extracted with ethyl acetate. The organic layer was washedwith 5% aqueous sodium hydrogencarbonate solution and saturated brine,dried over anhydrous sodium sulfate, and filtrated. The solvent wasevaporated under reduced pressure, and the residue was purified by NHsilica gel column chromatography (ethyl acetate/hexane=50/50→100/0). Thesolvent was evaporated under reduced pressure and the obtained solid waswashed with diisopropyl ether to give the title compound (0.79 g, 31%)as a yellow powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.69-0.88 (4H, m), 1.84-1.97 (1H, m), 5.52(2H, s), 6.45 (1H, dd, J=8.7, 2.7 Hz), 6.50 (1H, d, J=2.7 Hz), 7.03 (1H,d, J=9.0 Hz), 7.29 (1H, d, J=8.7 Hz), 7.94 (1H, s), 8.03 (1H, d, J=9.0Hz), 11.07 (1H, s).

Example 375 Production ofN-[4-bromo-3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-3-(1-cyano-1-methylethyl)benzamide

Using 3-(1-cyano-1-methylethyl)benzoic acid (330 mg, 1.8 mmol), oxalylchloride (170 μL, 2.0 mmol), N,N-dimethylformamide (1 drop),tetrahydrofuran (15 mL),N-[6-(5-amino-2-bromophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(650 mg, 1.7 mmol) and N,N-dimethylacetamide (5.0 mL) as startingmaterials and in the same manner as in Example 335, the title compound(800 mg, 85%) was obtained as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.71-0.88 (4H, m), 1.74 (6H, s), 1.85-1.96(1H, m), 7.16 (1H, d, J=9.6 Hz), 7.60 (1H, t, J=7.8 Hz), 7.64-7.71 (1H,m), 7.73-7.81 (2H, m), 7.83-7.97 (3H, m), 8.02 (1H, s), 8.10 (1H, d,J=9.6 Hz), 10.56 (1H, s), 11.10 (1H, s).

Example 376 Production ofN-{6-[3-({[(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)amino]carbonyl}amino)phenoxy]imidazo[1,2-b]pyridazin-2-yl}cyclopropanecarboxamide

To a solution ofN-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(160 mg, 0.52 mmol) and 2,2,2-trichloroethyl(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)carbamate (200 mg, 0.52 mmol) indimethylsulfoxide/water (2.0 mL/1.5 mL) was added triethylamine (53 mg,0.52 mmol), and the mixture was stirred at 85° C. for 8 hr. The reactionmixture was diluted with ethyl acetate, washed with 1N hydrochloricacid, 5% aqueous sodium hydrogencarbonate solution and saturated brine,dried over anhydrous sodium sulfate, and filtrated. The solvent wasevaporated under reduced pressure, and the residue was purified by NHsilica gel column chromatography (ethyl acetate/hexane=50/50→100/0) andprecipitated from ethyl acetate/diisopropyl ether/hexane to give thetitle compound (285 mg, 99%) as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.75-0.86 (4H, m), 1.85-2.02 (1H, m), 3.32(9H, s), 6.35 (1H, s), 6.84 (1H, dd, J=7.8, 1.8 Hz), 7.03 (1H, d, J=9.6Hz), 7.16 (1H, dd, J=8.1, 1.2 Hz), 7.28-7.46 (3H, m), 7.48-7.58 (4H, m),7.96 (1H, s), 8.03 (1H, d, J=9.6 Hz), 8.46 (1H, s), 9.22 (1H, s), 11.08(1H, s).

Example 377 Production ofN-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-6-(trifluoromethyl)pyridine-2-carboxamide

To a solution ofN-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(95 mg, 0.307 mmol) in N,N-dimethylformamide (5 mL) were added6-(trifluoromethyl)pyridine-2-carboxylic acid (65 mg, 0.337 mmol),N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (65 mg,0.337 mmol) and 1-hydroxybenzotriazole (46 mg, 0.337 mmol), and themixture was stirred at room temperature for 2 hr. Saturated aqueousammonium chloride solution was added to the reaction mixture. Themixture was extracted with ethyl acetate, and the organic layer waswashed with saturated brine, dried over anhydrous magnesium sulfate, andfiltrated. The solvent was evaporated under reduced pressure, and theresidue was washed with ethyl acetate/diisopropyl ether to give thetitle compound (126 mg, 85%) as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.76-0.84 (4H, m), 1.87-1.98 (1H, m),7.03-7.11 (2H, m), 7.47 (1H, t, J=8.2 Hz), 7.75-7.81 (1H, m), 7.83 (1H,t, J=2.2 Hz), 7.98 (1H, s), 8.06 (1H, d, J=9.2 Hz), 8.18 (1H, dd, J=6.9,2.0 Hz), 8.31-8.41 (2H, m), 10.56 (1H, s), 11.09 (1H, s).

Example 378 Production ofN-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-2-(trifluoromethyl)nicotinamide

To a solution ofN-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(95 mg, 0.307 mmol) in N,N-dimethylformamide (5 mL) were added2-(trifluoromethyl)nicotinic acid (65 mg, 0.337 mmol),N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (65 mg,0.337 mmol) and 1-hydroxybenzotriazole (46 mg, 0.337 mmol), and themixture was stirred at room temperature for 2 hr, heated to 50° C. andstirred for 2 hr. Saturated aqueous ammonium chloride solution was addedto the reaction mixture, and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine, dried overanhydrous magnesium sulfate, and filtrated. The solvent was evaporatedunder reduced pressure, and the residue was purified by silica gelcolumn chromatography (ethyl acetate/hexane=20/80→100/0), andprecipitated from ethyl acetate/diisopropyl ether to give the titlecompound (79.6 mg, 54%) as a pale-green powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.76-0.85 (4H, m), 1.87-1.98 (1H, m),7.01-7.11 (2H, m), 7.41-7.53 (2H, m), 7.62 (1H, t, J=2.0 Hz), 7.82-7.89(1H, m), 7.94-7.99 (1H, m), 8.05 (1H, d, J=9.6 Hz), 8.25 (1H, d, J=7.5Hz), 8.86 (1H, d, J=4.7 Hz), 10.85 (1H, s), 11.09 (1H, s).

Example 379 Production of2,6-dichloro-N-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]isonicotinamide

UsingN-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(95 mg, 0.307 mmol), 2,6-dichloropyridine-4-carboxylic acid (65 mg,0.337 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimidehydrochloride (65 mg, 0.337 mmol), 1-hydroxybenzotriazole (46 mg, 0.337mmol) and N,N-dimethylformamide (5 mL) as starting materials and in thesame manner as in Example 377, the title compound (124 mg, 84%) wasobtained as a pale-green powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.77-0.84 (4H, m), 1.87-1.98 (1H, m),7.04-7.11 (2H, m), 7.47 (1H, t, J=8.2 Hz), 7.60-7.65 (1H, m), 7.68 (1H,t, J=2.1 Hz), 7.96-8.02 (3H, m), 8.06 (1H, d, J=9.2 Hz), 10.73 (1H, s),11.09 (1H, s).

Example 380 Production of2-chloro-N-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-6-methylisonicotinamide

To a solution ofN-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(95 mg, 0.307 mmol) in N,N-dimethylformamide (5 mL) were added2-chloro-6-methylpyridine-4-carboxylic acid (58 mg, 0.337 mmol),N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (65 mg,0.337 mmol) and 1-hydroxybenzotriazole (46 mg, 0.337 mmol), and themixture was stirred at room temperature for 2 hr. Saturated aqueousammonium chloride solution was added to the reaction mixture, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, dried over anhydrous magnesium sulfate, andfiltrated. The solvent was evaporated under reduced pressure, and theresidue was purified by silica gel column chromatography (ethylacetate/hexane=3/97→100/0) and precipitated from ethyl acetate/hexane togive the title compound (115 mg, 82%) as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.77-0.83 (4H, m), 1.86-1.98 (1H, m), 2.55(3H, s), 7.01-7.11 (2H, m), 7.46 (1H, t, J=8.2 Hz), 7.60-7.79 (4H, m),7.98 (1H, s), 8.06 (1H, d, J=9.6 Hz), 10.64 (1H, s), 11.09 (1H, s).

Example 381 Production ofN-(3-{[2-(propionylamino)imidazo[1,2-b]pyridazin-6-yl]oxy}phenyl)-3-(trifluoromethyl)benzamide

UsingN-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide(150 mg, 0.363 mmol), propionic acid (40 μL, 0.544 mmol),N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (104 mg,0.544 mmol), 1-hydroxybenzotriazole (73 mg, 0.544 mmol), triethylamine(76 μL, 0.544 mmol) and N,N-dimethylformamide (5 mL) as startingmaterials and in the same manner as in Example 380, the title compound(116 mg, 68%) was obtained as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.07 (3H, t, J=7.5 Hz), 2.37 (2H, q, J=7.5Hz), 7.01-7.11 (2H, m), 7.46 (1H, t, J=8.2 Hz), 7.65-7.83 (3H, m),7.94-8.00 (1H, m), 8.02 (1H, s), 8.05 (1H, d, J=9.6 Hz), 8.22-8.30 (2H,m), 10.59 (1H, s), 10.75 (1H, s).

Example 382 Production ofN-(3-{[2-(isobutyrylamino)imidazo[1,2-b]pyridazin-6-yl]oxy}phenyl)-3-(trifluoromethyl)benzamide

UsingN-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide(150 mg, 0.363 mmol), 2-methylpropanoic acid (50 μL, 0.544 mmol),N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (104 mg,0.544 mmol), 1-hydroxybenzotriazole (73 mg, 0.544 mmol), triethylamine(76 μL, 0.544 mmol) and N,N-dimethylformamide (5 ml) as startingmaterials and in the same manner as in Example 380, the title compound(74 mg, 42%) was obtained as a pale-green powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.08 (6H, d, J=7.0 Hz), 2.65-2.77 (1H, m),7.00-7.11 (2H, m), 7.46 (1H, t, J=8.1 Hz), 7.63-7.83 (3H, m), 7.94-8.09(3H, m), 8.22-8.30 (2H, m), 10.59 (1H, s), 10.75 (1H, s).

Example 383 Production ofN-{3-[(2-{[(methylsulfonyl)acetyl]amino}imidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide

UsingN-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide(150 mg, 0.363 mmol), (methylsulfonyl)acetic acid (75 mg, 0.544 mmol),N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (104 mg,0.544 mmol), 1-hydroxybenzotriazole (73 mg, 0.544 mmol), triethylamine(76 μL, 0.544 mmol) and N,N-dimethylformamide (5 mL) as startingmaterials and in the same manner as in Example 377, the title compound(171 mg, 88%) was obtained as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 3.16 (3H, s), 4.37 (2H, m), 7.05 (1H, dd,J=8.1, 2.0 Hz), 7.14 (1H, d, J=9.6 Hz), 7.47 (1H, t, J=8.1 Hz),7.65-7.83 (3H, m), 7.94-8.01 (1H, m), 8.06 (1H, s), 8.12 (1H, d, J=9.6Hz), 8.22-8.30 (2H, m), 10.60 (1H, s), 11.29 (1H, s).

Example 384 Production ofN-[3-({2-[(2,2-dimethylpropanoyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-3-(trifluoromethyl)benzamide

To a solution ofN-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide(150 mg, 0.363 mmol) in pyridine (5 mL) was added dropwise2,2-dimethylpropanoyl chloride (49 μL, 0.399 mmol), and the mixture wasstirred at room temperature for 16 hr. Saturated aqueous sodiumhydrogencarbonate solution was added to the reaction mixture, and themixture was extracted with ethyl acetate. The extract was washed withsaturated brine, dried over anhydrous magnesium sulfate, and filtrated.The solvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography (ethylacetate/hexane=0/100→50/50), and precipitated from ethyl acetate/hexaneto give the title compound (90 mg, 50%) as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.22 (9H, s), 6.99-7.12 (2H, m), 7.46 (1H,t, J=8.2 Hz), 7.63-7.84 (3H, m), 7.98 (1H, d, J=7.9 Hz), 8.05 (2H, m),8.22-8.30 (2H, m), 10.36 (1H, s), 10.60 (1H, s)

Example 385 Production of 2,2,2-trichloroethyl[6-(3-{[3-(trifluoromethyl)benzoyl]amino}phenoxy)imidazo[1,2-b]pyridazin-2-yl]carbamate

To a solution ofN-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide(400 mg, 0.967 mmol) in tetrahydrofuran (10 mL) were added dropwise2,2,2-trichloroethyl chlorocarbonate (159 μL, 1.16 mmol) andtriethylamine (202 μL, 1.45 mmol), and the mixture was stirred at roomtemperature for 16 hr. The solvent was evaporated under reducedpressure, and the residue was washed with diisopropyl ether and water togive the title compound (436 mg, 76%) as a pale-yellow powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 4.97 (2H, s), 7.01-7.14 (2H, m), 7.46 (1H,t, J=8.0 Hz), 7.64-7.88 (4H, m), 7.98 (1H, d, J=8.0 Hz), 8.08 (1H, d,J=9.6 Hz), 8.22-8.30 (2H, m), 10.59 (1H, s), 10.97 (1H, s).

Example 386 Production ofN-[6-(3-{[3-(trifluoromethyl)benzoyl]amino}phenoxy)imidazo[1,2-b]pyridazin-2-yl]morpholine-4-carboxamide

A mixture of 2,2,2-trichloroethyl[6-(3-{[3-(trifluoromethyl)benzoyl]amino}phenoxy)imidazo[1,2-b]pyridazin-2-yl]carbamate(140 mg, 0.237 mmol), morpholine (31 mL, 0.356 mmol),N,N-diisopropylpropan-2-amine (123 μL, 0.713 mmol) and dimethylsulfoxide (10 mL) was heated to 80° C. and the mixture was stirred for24 hr. After the reaction mixture was allowed to cool to roomtemperature, saturated aqueous sodium hydrogencarbonate solution wasadded to the reaction mixture, and the mixture was extracted with ethylacetate. The extract was washed with water and saturated brine, driedover anhydrous magnesium sulfate, and filtrated. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography (ethyl acetate/hexane=50/50→100/0) andprecipitated from diisopropyl ether to give the title compound (92 mg,73%) as a pale-green powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 3.41-3.49 (4H, m), 3.58 (4H, m), 6.98-7.06(2H, m), 7.46 (1H, t, J=8.1 Hz), 7.64-7.83 (3H, m), 7.89 (1H, s),7.93-8.03 (2H, m), 8.20-8.32 (2H, m), 9.56 (1H, s), 10.59 (1H, s).

Example 387 Production of4-methyl-N-[6-(3-{[3-(trifluoromethyl)benzoyl]amino}phenoxy)imidazo[1,2-b]pyridazin-2-yl]piperazine-1-carboxamide

Using 2,2,2-trichloroethyl[6-(3-{[3-(trifluoromethyl)benzoyl]amino}phenoxy)imidazo[1,2-b]pyridazin-2-yl]carbamate(140 mg, 0.237 mmol), 1-methylpiperazine (40 μL, 0.356 mmol),N,N-diisopropylpropan-2-amine (123 μL, 0.713 mmol) and dimethylsulfoxide (10 mL) as starting materials and in the same manner as inExample 386, the title compound (65 mg, 50%) was obtained as apale-yellow powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 2.18 (3H, s), 2.25-2.32 (4H, m), 3.41-3.49(4H, m), 6.98-7.06 (2H, m), 7.46 (1H, t, J=8.1 Hz), 7.63-7.83 (3H, m),7.88 (1H, s), 7.94-8.03 (2H, m), 8.22-8.30 (2H, m), 9.51 (1H, s), 10.59(1H, s).

Example, 388 Production ofN-[3-({2-[(cyclobutylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-3-(trifluoromethyl)benzamide

To a solution ofN-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide(150 mg, 0.362 mmol) in tetrahydrofuran (5 mL) were added dropwisetriethylamine (75 μL, 0.544 mmol) and cyclobutanecarbonyl chloride (50μL, 0.435 mmol), and the mixture was stirred at room temperature for 16hr. Saturated aqueous ammonium chloride solution was added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theextract was dried over anhydrous magnesium sulfate, and filtrated. Thesolvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography (ethylacetate/hexane=50/50→100/0) to give the title compound (98 mg, 54%) as awhite powder.

¹H-NMR (CDCl₃, 300 MHz) δ 1.83-2.11 (2H, m), 2.15-2.46 (4H, m),3.14-3.28 (1H, m), 6.88 (1H, d, J=9.4 Hz), 7.00-7.06 (1H, m), 7.42-7.48(2H, m), 7.60-7.68 (1H, m), 7.69-7.85 (4H, m), 7.91-7.98 (1H, m),8.04-8.09 (1H, m), 8.13 (1H, s), 8.19 (1H, s).

Example 389 Production ofN-[3-({2-[(methylsulfonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-3-(trifluoromethyl)benzamide

UsingN-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide(150 mg, 0.362 mmol), triethylamine (76 μL, 0.544 mmol), methanesulfonylchloride (34 μL, 0.435 mmol) and tetrahydrofuran (5 mL) as startingmaterials and in the same manner as in Example 388, the title compound(108 mg, 61%) was obtained as a pale-green-powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 3.13 (3H, s), 7.05 (1H, dd, J=8.0, 1.6 Hz),7.14 (1H, d, J=9.6 Hz), 7.46 (1H, t, J=8.0 Hz), 7.63-7.84 (4H, m), 7.98(1H, d, J=8.0 Hz), 8.10 (1H, d, J=9.6 Hz), 8.22-8.30 (2H, m), 10.29 (1H,s), 10.60 (1H, s).

Example 390 Production of6-chloro-N-[6-(3-{[3-(trifluoromethyl)benzoyl]amino}phenoxy)imidazo[1,2-b]pyridazin-2-yl]nicotinamide

UsingN-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide(150 mg, 0.362 mmol), triethylamine (76 μL, 0.544 mmol),6-chloronicotinoyl chloride (76 mg, 0.435 mmol) and tetrahydrofuran (5mL) as starting materials and in the same manner as in Example 388, thetitle compound (155 mg, 77%) was obtained as a pale-yellow powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 7.07 (1H, dd, J=8.2, 1.8 Hz), 7.15 (1H, d,J=9.7 Hz), 7.48 (1H, t, J=8.2 Hz), 7.69 (2H, d, J=8.5 Hz), 7.74-7.84(2H, m), 7.98 (1H, d, J=7.7 Hz), 8.14 (1H, d, J=9.7 Hz), 8.20-8.33 (3H,m), 8.43 (1H, dd, J=8.5, 2.4 Hz), 9.03 (1H, d, J=2.4 Hz), 10.61 (1H, s),11.66 (1H, s).

Example 391 Production ofN-(3-{[2-({[2-(2-hydroxyethoxy)ethyl]carbamoyl}amino)imidazo[1,2-b]pyridazin-6-yl]oxy}phenyl)-3-(trifluoromethyl)benzamide

Using 2,2,2-trichloroethyl[6-(3-{[3-(trifluoromethyl)benzoyl]amino}phenoxy)imidazo[1,2-b]pyridazin-2-yl]carbamate(140 mg, 0.237 mmol), 2-(2-aminoethoxy)ethanol (43 μL, 0.435 mmol),N,N-diisopropylpropane-2-amine (76 μL, 0.435 mmol) and dimethylsulfoxide (5 mL) as starting materials and in the same manner as inExample 386, the title compound (86 mg, 62%) was obtained as apale-yellow powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 3.40-3.67 (8H, m), 4.58 (1H, t, J=5.4 Hz),6.67 (1H, brs), 7.01 (2H, d, J=9.4 Hz), 7.45 (1H, t, J=8.0 Hz),7.63-7.83 (4H, m), 7.93-8.02 (2H, m), 8.21-8.30 (2H, m), 9.11 (1H, s),10.58 (1H, s).

Example 392 Production ofN-{3-[(2-acetamidoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide

UsingN-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide(150 mg, 0.362 mmol), acetyl chloride (31 μL, 0.435 mmol) and pyridine(3 mL) as starting materials and in the same manner as in Example 384,the title compound (99 mg, 60%) was obtained as a pale-yellow powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 2.07 (3H, s), 7.01-7.11 (2H, m), 7.46 (1H,t, J=8.1 Hz), 7.63-7.83 (3H, m), 7.95-8.01 (2H, m), 8.06 (1H, d, J=9.6Hz), 8.22-8.30 (2H, m), 10.59 (1H, s), 10.80 (1H, s).

Example 393 Production ofN-[3-({2-[(cyclopentylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-3-(trifluoromethyl)benzamide

UsingN-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide(150 mg, 0.362 mmol), cyclopentanecarbonyl chloride (53 μL, 0.435 mmol),triethylamine (75 μL, 0.544 mmol) and tetrahydrofuran (5 mL) as startingmaterials and in the same manner as in Example 388, the title compound(105 mg, 57%) was obtained as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.47-1.90 (8H, m), 2.81-2.95 (1H, m),7.00-7.10 (2H, m), 7.46 (1H, t, J=8.2 Hz), 7.63-7.83 (3H, m), 7.94-8.09(3H, m), 8.21-8.30 (2H, m), 10.59 (1H, s), 10.77 (1H, s).

Example 394 Production ofN-[3-({2-[(3-hydroxypropanoyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-3-(trifluoromethyl)benzamide

To a solution ofN-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide(150 mg, 0.362 mmol) and 3-hydroxypropanoic acid (131 mg, 0.435 mmol) inN,N-dimethylformamide (5 mL) was added4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride(160 mg, 0.544 mmol), and the mixture was stirred at room temperaturefor 16 hr. Saturated aqueous ammonium chloride solution was added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theextract was washed with saturated brine, dried over anhydrous magnesiumsulfate, and filtrated. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography (ethyl acetate/hexane=30/70→100/0) and precipitated fromethanol to give the title compound (30 mg, 17%) as a pale-green powder.

¹H-NMR (CDCl₃, 300 MHz) δ 2.63-2.70 (2H, m), 3.73 (1H, brs), 3.96-4.03(2H, m), 6.89 (1H, d, J=9.4 Hz), 7.01-7.07 (1H, m), 7.42-7.48 (2H, m),7.59-7.86 (4H, m), 7.95 (1H, s), 8.07 (1H, d, J=7.9 Hz), 8.11-8.17 (2H,m), 8.54 (1H, s).

Example 395 Production of2-oxo-2-{[6-(3-{[3-(trifluoromethyl)benzoyl]amino}phenoxy)imidazo[1,2-b]pyridazin-2-yl]amino}ethylacetate

UsingN-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide(300 mg, 0.725 mmol), triethylamine (152 μL, 1.08 mmol),2-chloro-2-oxoethyl acetate (94 μL, 0.870 mmol) and tetrahydrofuran (7mL) as starting materials and in the same manner as in Example 388, thetitle compound (299 mg, 80%) was obtained as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 2.11 (3H, s), 4.70 (2H, s), 7.04 (1H, dd,J=8.6, 2.0 Hz), 7.11 (1H, d, J=9.8 Hz), 7.46 (1H, t, J=8.0 Hz),7.64-7.83 (3H, m), 7.94-8.02 (2H, m), 8.09 (1H, d, J=9.8 Hz), 8.22-8.30(2H, m), 10.59 (1H, s), 11.03 (1H, s).

Example 396 Production ofN-(3-{[2-(glycoloylamino)imidazo[1,2-b]pyridazin-6-yl]oxy}phenyl)-3-(trifluoromethyl)benzamide

A mixture of2-oxo-2-{[6-(3-{[3-(trifluoromethyl)benzoyl]amino}phenoxy)imidazo[1,2-b]pyridazin-2-yl]amino}ethylacetate (250 mg, 0.486 mmol), 1N aqueous sodium hydroxide solution (3mL) and methanol (5 mL) was stirred at room temperature for 3 hr. Thereaction mixture was neutralized by the addition of 1N hydrochloricacid, and extracted with ethyl acetate. The extract was washed withsaturated brine, dried over anhydrous magnesium sulfate, and filtrated.The solvent was evaporated under reduced pressure, and the residue waswashed with ethanol to give the title compound (185 mg, 81%) as a whitepowder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 4.02-4.08 (2H, m), 5.46-5.55 (1H, m), 7.05(1H, dd, J=7.6, 2.2 Hz), 7.11 (1H, d, J=9.6 Hz), 7.47 (1H, t, J=8.0 Hz),7.64-7.83 (3H, m), 7.98 (1H, d, J=8.0 Hz), 8.03-8.12 (2H, m), 8.22-8.30(2H, m), 10.23 (1H, s), 10.60 (1H, s).

Example 397 Production ofN-[3-({2-[(chloroacetyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-3-(trifluoromethyl)benzamide

To a solution ofN-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide(500 mg, 1.20 mmol) in tetrahydrofuran (10 mL) were added chloroacetylchloride (168 μL, 1.45 mmol) and triethylamine (253 μL, 1.81 mmol), andthe mixture was stirred at room temperature for 16 hr. Saturated aqueousammonium chloride solution was added to the reaction mixture, and themixture was extracted with ethyl acetate. The extract was washed withsaturated brine, dried over anhydrous magnesium sulfate, and filtrated.The solvent was evaporated under reduced pressure, and the residue waswashed with ethanol to give the title compound (418 mg, 71%) as apale-yellow powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 4.31 (2H, s), 7.05 (1H, dd, J=8.2, 2.4 Hz),7.12 (1H, d, J=9.4 Hz), 7.47 (1H, t, J=8.2 Hz), 7.64-7.84 (3H, m),7.93-8.13 (3H, m), 8.21-8.30 (2H, m), 10.59 (1H, s), 11.20 (1H, s).

Example 398 Production ofN-[3-({2-[(N,N-dimethylglycyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-3-(trifluoromethyl)benzamide

A mixture ofN-[3-({2-[(chloroacetyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-3-(trifluoromethyl)benzamide(120 mg, 0.244 mmol), aqueous dimethylamine (3 mL) solution andacetonitrile (3 mL) was heated to 80° C. and stirred for 3 hr. After thereaction mixture was allowed to cool to room temperature, saturatedaqueous sodium hydrogencarbonate solution was added to the reactionmixture, and the mixture was extracted with ethyl acetate. The extractwas washed with saturated brine, dried over anhydrous magnesium sulfate,and filtrated. The solvent was evaporated under reduced pressure, andthe residue was washed with ethanol to give the title compound (85 mg,70%) as a pale-yellow powder.

¹H-NMR (CDCl₃, 300 MHz) δ 2.37 (6H, s), 3.11 (2H, s), 6.88 (1H, d, J=9.6Hz), 6.99-7.06 (1H, m), 7.39-7.50 (2H, m), 7.63 (1H, t, J=7.9 Hz),7.69-7.72 (1H, m), 7.75 (1H, d, J=9.6 Hz), 7.81 (1H, d, J=7.9 Hz), 8.00(1H, s), 8.06 (1H, d, J=7.5 Hz), 8.13 (1H, s), 8.21 (1H, s), 9.65 (1H,brs).

Example 399 Production of N-[3-({2-[(morpholin4-ylacetyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-3-(trifluoromethyl)benzamide

UsingN-[3-({2-[(chloroacetyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-3-(trifluoromethyl)benzamide(120 mg, 0.244 mmol), morpholine (1 mL) and acetonitrile (3 mL) asstarting materials and in the same manner as in Example 398, the titlecompound (116 mg, 87%) was obtained as a white powder.

¹H-NMR (CDCl₃, 300 MHz) δ 2.59-2.65 (4H, m), 3.18 (2H, s), 3.75-3.82(4H, m), 6.90 (1H, d, J=9.6 Hz), 7.01-7.07 (1H, m), 7.42-7.46 (2H, m),7.59-7.68 (1H, m), 7.71-7.85 (3H, m), 7.92-7.98 (1H, m), 8.06 (1H, d,J=7.9 Hz), 8.13 (1H, s), 8.21 (1H, s), 9.50 (1H, s).

Example 400 Production ofN-{3-[(2-{[(4-methylpiperazin-1-yl)acetyl]amino}imidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide

UsingN-[3-({2-[(chloroacetyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-3-(trifluoromethyl)benzamide(120 mg, 0.244 mmol), 1-methylpiperazine (1 mL) and acetonitrile (2 mL)as starting materials and in the same manner as in Example 398, thetitle compound (67 mg, 50%) was obtained as a white powder.

¹H-NMR (CDCl₃, 300 MHz) δ 2.32 (3H, s), 2.43-2.74 (8H, m), 3.18 (2H, s),6.89 (1H, d, J=9.6 Hz), 7.00-7.07 (1H, m), 7.41-7.48 (2H, m), 7.64 (1H,t, J=7.8 Hz), 7.71-7.85 (3H, m), 7.96-8.01 (1H, m), 8.06 (1H, d, J=7.8Hz), 8.13 (1H, s), 8.21 (1H, s), 9.55 (1H, s).

Example 401 Production ofN-[3-({2-[(N-methylglycyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-3-(trifluoromethyl)benzamide

UsingN-[3-({2-[(chloroacetyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-3-(trifluoromethyl)benzamide(92 mg, 0.187 mmol), methylamine/methanol (2 mL) solution andacetonitrile (1 mL) as starting materials and in the same manner as inExample 398, the title compound (22 mg, 25%) was obtained as a whitepowder.

¹H-NMR (CDCl₃, 300 MHz) δ 2.50 (3H, s), 3.39 (2H, s), 6.88 (1H, d, J=9.4Hz), 7.03 (1H, dd, J=6.7, 2.0 Hz), 7.39-7.51 (2H, m), 7.59-7.85 (4H, m),7.93-8.10 (2H, m), 8.13 (1H, s), 8.20-8.25 (1H, m), 9.72 (1H, s).

Example 402 Production ofN-{3-[(2-acetamidoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(1-cyanocyclopropyl)benzamide

To a solution of 3-(1-cyanocyclopropyl)benzoic acid (1.50 g, 8.01 mmol)in tetrahydrofuran (30 mL) were added N,N-dimethylformamide (2 drops)and oxalyl chloride (1.16 mL, 13.3 mmol), and the mixture was stirred atroom temperature for 1.5 hr. The solvent was evaporated under reducedpressure, and the residue andN-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]acetamide (1.89 g,6.67 mmol) were dissolved in N-methylpyrrolidone (30 mL), and themixture was stirred at room temperature for 3 hr. Saturated aqueoussodium hydrogencarbonate solution was added to the reaction mixture, andthe mixture was extracted with ethyl acetate. The extract was washedwith saturated brine, dried over anhydrous magnesium sulfate andfiltrated, and the residue was purified by silica gel columnchromatography (ethyl acetate/hexane=0/100→100/0) to give the titlecompound (2.25 g, 75%) as a pale-brown powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.58-1.65 (2H, m), 1.77-1.84 (2H, m), 2.07(3H, s), 6.99-7.11 (2H, m), 7.45 (1H, t, J=8.2 Hz), 7.51-7.60 (2H, m),7.62-7.68 (1H, m), 7.72 (1H, t, J=2.1 Hz), 7.82 (1H, s), 7.84-7.90 (1H,m), 8.00 (1H, s), 8.05 (1H, d, J=9.6 Hz), 10.42 (1H, s), 10.80 (1H, s).

Example 403 Production ofN-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(1-cyanocyclopropyl)benzamide

A mixture ofN-{3-[(2-acetamidoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(1-cyanocyclopropyl)benzamide(2.20 g, 4.86 mmol), 4N hydrochloric acid-ethyl acetate solution (35 mL)and methanol (35 mL) was stirred at room temperature for 14 hr. Thereaction mixture was neutralized by the addition of 8N aqueous sodiumhydroxide solution and extracted with ethyl acetate. The extract waswashed with saturated brine, dried over anhydrous magnesium sulfate, andfiltrated. The solvent was evaporated under reduced pressure, and theresidue was washed with diisopropyl ether to give the title compound(1.63 g, 82%) as a yellow powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.58-1.64 (2H, m), 1.77-1.84 (2H, m), 5.34(2H, brs), 6.80 (1H, d, J=9.3 Hz), 6.91-6.97 (1H, m), 7.15 (1H, s), 7.41(1H, t, J=8.3 Hz), 7.51-7.67 (4H, m), 7.73 (1H, d, J=9.3 Hz), 7.81 (1H,s), 7.84-7.89 (1H, m), 10.38 (1H, s).

Example 404 Production of6-chloro-N-[6-(3-{[3-(1-cyanocyclopropyl)benzoyl]amino}phenoxy)imidazo[1,2-b]pyridazin-2-yl]nicotinamide

UsingN-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(1-cyanocyclopropyl)benzamide(120 mg, 0.292 mmol), 6-chloronicotinoyl chloride (61 mg, 0.350 mmol),triethylamine (62 μL, 0.438 mmol) and tetrahydrofuran (5 mL) as startingmaterials and in the same manner as in Example 385, the title compound(121 mg, 75%) was obtained as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.58-1.65 (2H, m), 1.78-1.84 (2H, m), 7.05(1H, dd, J=8.2, 1.8 Hz), 7.14 (1H, d, J=9.6 Hz), 7.47 (1H, t, J=8.2 Hz),7.52-7.60 (2H, m), 7.64-7.72 (2H, m), 7.73-7.77 (1H, m), 7.82 (1H, s),7.85-7.91 (1H, m), 8.13 (1H, d, J=9.6 Hz), 8.22 (1H, s), 8.43 (1H, dd,J=8.2, 2.4 Hz), 9.02 (1H, d, J=2.4 Hz), 10.44 (1H, s), 11.65 (1H, s).

Example 405 Production of2-{[6-(3-{[3-(1-cyanocyclopropyl)benzoyl]amino}phenoxy)imidazo[1,2-b]pyridazin-2-yl]amino}-2-oxoethylacetate

UsingN-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(1-cyanocyclopropyl)benzamide(200 mg, 0.487 mmol), triethylamine (101 μL, 0.730 mmol),2-chloro-2-oxoethyl acetate (63 μL, 0.584 mmol) and tetrahydrofuran (5mL) as starting materials and in the same manner as in Example 385, thetitle compound (183 mg, 74%) was obtained as a gray powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.58-1.65 (2H, m), 1.77-1.85 (2H, m), 2.11(3H, s), 4.70 (2H, s), 7.02 (1H, dd, J=7.9, 2.0 Hz), 7.10 (1H, d, J=9.6Hz), 7.45 (1H, t, J=7.9 Hz), 7.51-7.61 (2H, m), 7.66 (1H, d, J=7.9 Hz),7.72 (1H, t, J=2.0 Hz), 7.82 (1H, s), 7.84-7.90 (1H, m), 8.00 (1H, s),8.08 (1H, d, J=9.6 Hz), 10.42 (1H, s), 11.03 (1H, s).

Example 406 Production of3-(1-cyanocyclopropyl)-N-(3-{[2-(glycoloylamino)imidazo[1,2-b]pyridazin-6-yl]oxy}phenyl)benzamide

Using2-{[6-(3-{[3-(1-cyanocyclopropyl)benzoyl]amino}phenoxy)imidazo[1,2-b]pyridazin-2-yl]amino}-2-oxoethylacetate (130 mg, 0.254 mmol), 1N aqueous sodium hydroxide solution (1.5mL) and methanol (3 mL) as starting materials and in the same manner asin Example 396, the title compound (59 mg, 50%) was obtained as apale-yellow powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.58-1.64 (2H, m), 1.78-1.84 (2H, m),4.02-4.08 (2H, m), 5.47-5.54 (1H, m), 7.03 (1H, dd, J=8.0, 2.0 Hz), 7.10(1H, d, J=9.6 Hz), 7.45 (1H, t, J=8.0 Hz), 7.53-7.59 (2H, m), 7.63-7.69(1H, m), 7.73 (1H, t, J=2.0), 7.81 (1H, d, J=2.0), 7.84-7.90 (1H, m),8.03-8.11 (2H, m), 10.22 (1H, s), 10.42 (1H, s).

Example 407 Production ofN-[3-({2-[(chloroacetyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-3-(1-cyanocyclopropyl)benzamide

UsingN-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(1-cyanocyclopropyl)benzamide(600 mg, 1.46 mmol), triethylamine (305 μL, 2.19 mmol), chloroacetylchloride (202 μL, 1.75 mmol) and tetrahydrofuran (10 mL) as startingmaterials and in the same manner as in Example 385, the title compound(636 mg, 89%) was obtained as a gray powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.57-1.65 (2H, m), 1.77-1.85 (2H, m), 4.31(2H, s), 7.03 (1H, dd, J=8.0, 2.2 Hz), 7.12 (1H, d, J=9.6 Hz), 7.45 (1H,t, J=8.0 Hz), 7.52-7.60 (2H, m), 7.66 (1H, d, J=8.0 Hz), 7.73 (1H, t,J=2.2 Hz), 7.82 (1H, s), 7.85-7.91 (1H, m), 8.04 (1H, s), 8.09 (1H, d,J=9.6 Hz), 10.43 (1H, s), 11.20 (1H, s).

Example 408 Production of3-(1-cyanocyclopropyl)-N-{3-[(2-{[(4-methylpiperazin-1-yl)acetyl]amino}imidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}benzamide

A mixture ofN-[3-({2-[(chloroacetyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-3-(1-cyanocyclopropyl)benzamide(140 mg, 0.287 mmol), 1-methylpiperazine (1 mL) and acetonitrile (2 mL)was stirred with heating at 80° C. for 4 hr. After the reaction mixturewas allowed to cool to room temperature, saturated aqueous sodiumhydrogencarbonate solution was added to the reaction mixture, and themixture was extracted with ethyl acetate. The extract was washed withsaturated brine, dried over anhydrous magnesium sulfate, and filtrated.The solvent was evaporated under reduced pressure, and the residue waspurified by NH silica gel column chromatography (ethylacetate/hexane=0/100→100/0) to give the title compound (65 mg, 41%) as awhite powder.

¹H-NMR (CDCl₃, 300 MHz) δ 1.43-1.53 (2H, m), 1.75-1.83 (2H, m), 2.32(3H, s), 2.40-2.72 (8H, m), 3.18 (2H, s), 6.89 (1H, d, J=9.6 Hz),6.98-7.05 (1H, m), 7.38-7.59 (4H, m), 7.69-7.80 (4H, m), 8.01 (1H, s),8.21 (1H, s), 9.55 (1H, s).

Example 409 Production of3-(1-cyanocyclopropyl)-N-[3-({2-[(morpholin-4-ylacetyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]benzamide

UsingN-[3-({2-[(chloroacetyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-3-(1-cyanocyclopropyl)benzamide(140 mg, 0.287 mmol), morpholine (1 mL) and acetonitrile (2 mL) asstarting materials and in the same manner as in Example 408, the titlecompound (123 mg, 79%) was obtained as a white powder.

¹H-NMR (CDCl₃, 300 MHz) δ 1.45-1.52 (2H, m), 1.75-1.82 (2H, m),2.59-2.66 (4H, m), 3.18 (2H, s), 3.75-3.82 (4H, m), 6.90 (1H, d, J=9.4Hz), 6.98-7.05 (1H, m), 7.37-7.59 (4H, m), 7.70-7.79 (4H, m), 8.02 (1H,s), 8.20 (1H, s), 9.50 (1H, s).

Example 410 Production of methyl[6-(3-{[3-(trifluoromethyl)benzoyl]amino}phenoxy)imidazo[1,2-b]pyridazin-2-yl]carbamate

UsingN-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide(150 mg, 0.362 mmol), methyl chlorocarbonate (33 μL, 0.435 mmol),triethylamine (75 μL, 0.544 mmol) and tetrahydrofuran (3 mL) as startingmaterials and in the same manner as in Example 388, the title compound(104 mg, 61%) was obtained as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 3.68 (3H, s), 7.01-7.09 (2H, m), 7.46 (1H,t, J=8.1 Hz), 7.64-7.84 (4H, m), 7.94-8.06 (2H, m), 8.22-8.30 (2H, m),10.40 (1H, brs), 10.58 (1H, s).

Example 411 Production of ethyl[6-(3-{[3-(trifluoromethyl)benzoyl]amino}phenoxy)imidazo[1,2-b]pyridazin-2-yl]carbamate

UsingN-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide(150 mg, 0.362 mmol), ethyl chlorocarbonate (41 μL, 0.435 mmol),triethylamine (75 μL, 0.544 mmol) and tetrahydrofuran (3 mL) as startingmaterials and in the same manner as in Example 388, the title compound(109 mg, 62%) was obtained as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.23 (3H, t, J=7.1 Hz), 4.14 (2H, q, J=7.1Hz), 7.00-7.09 (2H, m), 7.46 (1H, t, J=8.1 Hz), 7.63-7.84 (4H, m),7.94-8.06 (2H, m), 8.22-8.30 (2H, m), 10.33 (1H, brs), 10.58 (1H, s).

Example 412 Production ofN-[6-(3-{[3-(1-cyanocyclopropyl)benzoyl]amino}phenoxy)imidazo[1,2-b]pyridazin-2-yl]nicotinamide

To a solution of nicotinic acid (54 mg, 0.438 mmol) in tetrahydrofuran(3 mL) were added N,N-dimethylformamide (1 drop) and oxalyl chloride (64μL, 0.734 mmol), and the mixture was stirred at room temperature for 1hr. The solvent was evaporated under reduced pressure, and the residueandN-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(1-cyanocyclopropyl)benzamide(150 mg, 0.365 mmol) were dissolved in N-methylpyrrolidone (3 mL), andthe mixture was stirred at room temperature for 14 hr. Saturated aqueoussodium hydrogencarbonate solution was added to the reaction mixture, andthe mixture was extracted with ethyl acetate. The extract was washedwith saturated brine, dried over anhydrous magnesium sulfate, andfiltrated. The solvent was evaporated under reduced pressure, and theresidue was purified by silica gel column chromatography (ethylacetate/hexane=20/80→100/0) to give the title compound (100 mg, 53%) asa pale-green powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.57-1.65 (2H, m), 1.76-1.85 (2H, m), 7.05(1H, d, J=8.5 Hz), 7.14 (1H, d, J=9.6 Hz), 7.47 (1H, t, J=8.1 Hz),7.51-7.61 (3H, m), 7.63-7.93 (4H, m), 8.13 (1H, d, J=9.6 Hz), 8.24 (1H,s), 8.39 (1H, d, J=7.7 Hz), 8.75 (1H, d, J=4.9 Hz), 9.18 (1H, d, J=1.1Hz), 10.44 (1H, s), 11.57 (1H, s).

Example 413 Production ofN-[6-(3-{[3-(1-cyanocyclopropyl)benzoyl]amino}phenoxy)imidazo[1,2-b]pyridazin-2-yl]-6-methylnicotinamide

UsingN-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(1-cyanocyclopropyl)benzamide(150 mg, 0.365 mmol), 6-methylnicotinoyl chloride (75 mg, 0.548 mmol),N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (105 mg,0.548 mmol), 1-hydroxybenzotriazole (74 mg, 0.548 mmol) andN,N-dimethylformamide (5 mL) as starting materials and in the samemanner as in Example 380, the title compound (44 mg, 23%) was obtainedas a pale-green powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.59-1.65 (2H, m), 1.78-1.84 (2H, m), 2.55(3H, s), 7.03-7.07 (1H, m), 7.14 (1H, d, J=9.6 Hz), 7.40 (1H, d, J=8.2Hz), 7.47 (1H, t, J=8.2 Hz), 7.54-7.60 (2H, m), 7.65-7.69 (1H, m), 7.75(1H, t, J=2.2 Hz), 7.81-7.83 (1H, m), 7.86-7.90 (1H, m), 8.12 (1H, dd,J=9.6, 0.5 Hz), 8.22 (1H, s), 8.29 (1H, dd, J=8.2, 2.2 Hz), 9.08 (1H, d,J=2.2 Hz), 10.45 (1H, s), 11.50 (1H, s).

Example 414 Production ofN-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-2-(trifluoromethyl)benzamide

UsingN-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(150 mg, 0.484 mmol), 2-(trifluoromethyl)benzoic acid (110 mg, 0.581mmol), oxalyl chloride (84 mL, 0.969 mmol), N,N-dimethylformamide (1drop), tetrahydrofuran (5 mL) and N-methylpyrrolidone (5 mL) as startingmaterials and in the same manner as in Example 412, the title compound(175 mg, 75%) was obtained as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.77-0.84 (4H, m), 1.86-1.98 (1H, m),6.98-7.04 (1H, m), 7.07 (1H, d, J=9.6 Hz), 7.43 (1H, t, J=8.1 Hz),7.51-7.57 (1H, m), 7.64 (1H, t, J=2.1 Hz), 7.67-7.76 (2H, m), 7.76-7.88(2H, m), 7.98 (1H, s), 8.05 (1H, d, J=9.6 Hz), 10.71 (1H, s), 11.07 (1H,s).

Example 415 Production ofN-[4-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-3-(trifluoromethyl)benzamide

UsingN-[6-(4-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(150 mg, 0.484 mmol), 3-(trifluoromethyl)benzoic acid (110 mg, 0.581mmol), oxalyl chloride (84 μL, 0.969 mmol), N,N-dimethylformamide (1drop), tetrahydrofuran (5 mL) and N-methylpyrrolidone (5 mL) as startingmaterials and in the same manner as in Example 412, the title compound(57 mg, 24%) was obtained as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.76-0.84 (4H, m), 1.86-1.97 (1H, m), 7.05(1H, d, J=9.6 Hz), 7.29 (2H, d, J=8.9 Hz), 7.77-7.88 (3H, m), 7.94 (1H,s), 7.96-8.06 (2H, m), 8.25-8.32 (2H, m), 10.57 (1H, s), 11.06 (1H, s).

Example 416 Production ofN-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-1H-indazole-3-carboxamide

UsingN-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(150 mg, 0.484 mmol), 1H-indazole-3-carboxylic acid (94 mg, 0.581 mmol),oxalyl chloride (84 μL, 0.969 mmol), N,N-dimethylformamide (1 drop),tetrahydrofuran (5 mL) and N-methylpyrrolidone (5 mL) as startingmaterials and in the same manner as in Example 412, the title compound(149 mg, 68%) was obtained as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.76-0.84 (4H, m), 1.84-1.98 (1H, m), 6.98(1H, dd, J=7.6, 2.0 Hz), 7.07 (1H, d, J=9.6 Hz), 7.28 (1H, t, J=7.6 Hz),7.38-7.49 (2H, m), 7.66 (1H, d, J=8.3 Hz), 7.78-7.83 (1H, m), 7.88 (1H,t, J=2.0 Hz), 7.99 (1H, s), 8.05 (1H, d, J=9.6 Hz), 8.20 (1H, d, J=8.3Hz), 10.51 (1H, s), 11.08 (1H, s), 13.79 (1H, brs).

Example 417 Production ofN-[6-(3-{[3-(1-cyanocyclopropyl)benzoyl]amino}phenoxy)imidazo[1,2-b]pyridazin-2-yl]pyridine-2-carboxamide

UsingN-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(1-cyanocyclopropyl)benzamide(150 mg, 0.365 mmol), pyridine-2-carboxylic acid (54 mg, 0.438 mmol),oxalyl chloride (63 μL), N,N-dimethylformamide (1 drop), tetrahydrofuran(3 mL) and N-methylpyrrolidone (5 mL) as starting materials and in thesame manner as in Example 412, the title compound (125 mg, 67%) wasobtained as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.58-1.65 (2H, m), 1.78-1.85 (2H, m), 7.05(1H, dd, J=8.0, 1.8 Hz), 7.16 (1H, d, J=9.6 Hz), 7.47 (1H, t, J=8.0 Hz),7.52-7.61 (2H, m), 7.65-7.77 (3H, m), 7.83 (1H, s), 7.85-7.91 (1H, m),8.05-8.20 (3H, m), 8.24 (1H, s), 8.73-8.78 (1H, m), 10.44 (1H, s), 10.69(1H, s).

Example 418 Production ofN-[6-(3-{[3-(1-cyanocyclopropyl)benzoyl]amino}phenoxy)imidazo[1,2-b]pyridazin-2-yl]isonicotinamide

UsingN-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(1-cyanocyclopropyl)benzamide(150 mg, 0.365 mmol), pyridine-4-carboxylic acid (54 mg, 0.438 mmol),oxalyl chloride (63 μL, 0.734 mmol), N,N-dimethylformamide (1 drop),tetrahydrofuran (3 mL) and N-methylpyrrolidone (3 mL) as startingmaterials and in the same manner as in Example 412, the title compound(111 mg, 59%) was obtained as a pale-green powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.57-1.65 (2H, m), 1.77-1.85 (2H, m),7.01-7.09 (1H, m), 7.15 (1H, d, J=9.6 Hz), 7.47 (1H, t, J=8.2 Hz),7.51-7.61 (2H, m), 7.64-7.70 (1H, m), 7.75 (1H, t, J=2.1 Hz), 7.79-7.84(1H, m), 7.85-7.91 (1H, m), 7.93-7.98 (2H, m), 8.13 (1H, d, J=9.6 Hz),8.24 (1H, s), 8.73-8.81 (2H, m), 10.44 (1H, s), 11.67 (1H, s).

Example 419 Production ofN-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-1H-indole-2-carboxamide

UsingN-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(150 mg, 0.484 mmol), 1H-indole-2-carboxylic acid (93 mg, 0.581 mmol),oxalyl chloride (84 μL, 0.969 mmol), N,N-dimethylformamide (1 drop),tetrahydrofuran (5 mL) and N-methylpyrrolidone (3 mL) as startingmaterials and in the same manner as in Example 412, the title compound(153 mg, 70%) was obtained as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.76-0.85 (4H, m), 1.83-2.01 (1H, m),6.96-7.12 (3H, m), 7.18-7.26 (1H, m), 7.39-7.49 (3H, m), 7.69 (2H, t,J=8.1 Hz), 7.76 (1H, t, J=2.1 Hz), 8.00 (1H, s), 8.06 (1H, d, J=9.4 Hz),10.33 (1H, s), 11.09 (1H, s), 11.75 (1H, s).

Example 420 Production of6-cyano-N-[6-(3-{[3-(1-cyanocyclopropyl)benzoyl]amino}phenoxy)imidazo[1,2-b]pyridazin-2-yl]nicotinamide

A mixture of6-chloro-N-[6-(3-{[3-(1-cyanocyclopropyl)benzoyl]amino}phenoxy)imidazo[1,2-b]pyridazin-2-yl]nicotinamide(120 mg, 0.201 mmol), tetrakis(triphenylphosphine)palladium (0) (58 mg,50.4 mol), zinc cyanide (26 mg, 0.225 mmol) and N,N-dimethylformamide(2.5 mL) was stirred with heating under an argon atmosphere at 100° C.for 6.5 hr. After the reaction mixture was allowed to cool to roomtemperature, saturated aqueous sodium hydrogencarbonate solution wasadded to the mixture, and the mixture was extracted with ethyl acetate.The extract was washed with saturated brine, dried over anhydrousmagnesium sulfate, and filtrated. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography (ethyl acetate/hexane=50/50→100/0) to give the titlecompound (51 mg, 47%) as a yellow powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.58-1.65 (2H, m), 1.78-1.85 (2H, m), 7.05(1H, dd, J=8.2, 1.4 Hz), 7.16 (1H, d, J=9.6 Hz), 7.47 (1H, t, J=8.2 Hz),7.51-7.60 (2H, m), 7.67 (1H, d, J=8.5 Hz), 7.74-7.91 (3H, m), 8.14 (1H,d, J=9.6 Hz), 8.19-8.27 (2H, m), 8.60 (1H, dd, J=8.0, 2.0 Hz), 9.29 (1H,s), 10.45 (1H, s), 11.84 (1H, s).

Example 421 Production ofN-{6-[3-(but-2-ynoylamino)phenoxy]imidazo[1,2-b]pyridazin-2-yl}cyclopropanecarboxamide

To a solution of but-2-ynoic acid (61 mg, 0.581 mmol) in tetrahydrofuran(3 mL) were added isobutyl chlorocarbonate (76 μL, 0.581 mmol) and4-methylmorpholine (80 μL, 0.727 mmol), a solution ofN-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(150 mg, 0.484 mmol) in pyridine (1.5 mL)/N,N-dimethylformamide (2 mL)was further added under ice-cooling, and the mixture was stirred at roomtemperature for 3 hr. Saturated aqueous sodium hydrogencarbonatesolution was added to the reaction mixture, and the mixture wasextracted with ethyl acetate/tetrahydrofuran. The extract was washedwith saturated brine, dried over anhydrous sodium sulfate, andfiltrated. The solvent was evaporated under reduced pressure, and theresidue was washed with ethyl acetate to give the title compound (132mg, 73%) as a pale-orange powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.76-0.85 (4H, m), 1.86-1.97 (1H, m), 2.04(3H, s), 6.92-6.99 (1H, m), 7.04 (1H, d, J=9.6 Hz), 7.32-7.47 (2H, m),7.54 (1H, t, J=1.9 Hz), 7.93-7.99 (1H, m), 8.04 (1H, d, J=9.6 Hz), 10.75(1H, s), 11.08 (1H, s).

Example 422 Production ofN-{6-[3-(propioloylamino)phenoxy]imidazo[1,2-b]pyridazin-2-yl}cyclopropanecarboxamide

To a solution of propiolic acid (27 mg, 0.387 mmol) in tetrahydrofuran(2 mL) and N,N-dimethylformamide (2 mL) was addedN,N′-dicyclohexylcarbodiimide (100 mg, 0.484 mmol) under ice-cooling,and the mixture was stirred for 30 min. To the reaction mixture wasaddedN-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(100 mg, 0.323 mmol), and the mixture was stirred under ice-cooling for4 hr. The solvent was evaporated under reduced pressure, and the residuewas purified by silica gel column chromatography (ethylacetate/hexane=0/100→100/0) to give the title compound (24 mg, 21%) as apale-orange powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.75-0.85 (4H, m), 1.87-1.98 (1H, m), 4.45(1H, s), 6.97-7.08 (2H, m), 7.35-7.48 (2H, m), 7.51-7.57 (1H, m), 7.96(1H, s), 8.04 (1H, d, J=9.8 Hz), 10.95 (1H, s), 11.08 (1H, s).

Example 423 Production ofN-(6-{3-[(3-phenylprop-2-ynoyl)amino]phenoxy}imidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide

To a solution of 3-phenylprop-2-ynoic acid (85 mg, 0.581 mmol) intetrahydrofuran (3 mL) were added isobutyl chlorocarbonate (76 μL, 0.581mmol) and 4-methylmorpholine (80 μL, 0.727 mmol) under ice-cooling, asolution ofN-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(150 mg, 0.484 mmol) in N,N-dimethylformamide (3 mL) was further addedthereto, and the mixture was stirred at room temperature for 16 hr.Water was added to the reaction mixture, and the precipitated solid wasfiltrated and washed with water to give the title compound (188 mg, 89%)as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.77-0.84 (4H, m), 1.88-1.98 (1H, m),6.98-7.04 (1H, m), 7.06 (1H, d, J=9.5 Hz), 7.38-7.56 (5H, m), 7.59 (1H,t, J=2.0 Hz), 7.62-7.68 (2H, m), 7.98 (1H, s), 8.05 (1H, d, J=9.5 Hz),11.01 (1H, s), 11.08 (1H, s).

Example 424 Production ofN-[6-(3-{[3-(1-cyanocyclopropyl)benzoyl]amino}phenoxy)imidazo[1,2-b]pyridazin-2-yl]-6-fluoronicotinamide

UsingN-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(1-cyanocyclopropyl)benzamide(150 mg, 0.365 mmol), 6-fluoronicotinic acid (61 mg, 0.438 mmol), oxalylchloride (64 μL, 0.730 mmol), N,N-dimethylformamide (1 drop),tetrahydrofuran (3 mL) and N,N-dimethylacetamide (3 mL) as startingmaterials and in the same manner as in Example 412, the title compound(38 mg, 20%) was obtained as a pale-green powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.57-1.65 (2H, m), 1.78-1.85 (2H, m), 7.05(1H, dd, J=8.2, 2.2 Hz), 7.15 (1H, d, J=9.5 Hz), 7.35 (1H, dd, J=8.2,2.8 Hz), 7.47 (1H, t, J=8.2 Hz), 7.52-7.60 (2H, m), 7.64-7.69 (1H, m),7.75 (1H, t, J=2.2 Hz), 7.80-7.84 (1H, m), 7.85-7.91 (1H, m), 8.13 (1H,d, J=9.5 Hz), 8.22 (1H, s), 8.55-8.63 (1H, m), 8.90 (1H, d, J=2.2 Hz),10.45 (1H, s), 11.61 (1H, s).

Example 425 Production ofN-[6-(3-{[3-(1-cyanocyclopropyl)benzoyl]amino}phenoxy)imidazo[1,2-b]pyridazin-2-yl]-6-(trifluoromethyl)nicotinamide

UsingN-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(1-cyanocyclopropyl)benzamide(150 mg, 0.365 mmol), 6-(trifluoromethyl)nicotinic acid (83 mg, 0.438mmol), oxalyl chloride (64 μL, 0.730 mmol), N,N-dimethylformamide (1drop), tetrahydrofuran (3 mL) and N,N-dimethylacetamide (3 mL) asstarting materials and in the same manner as in Example 412, the titlecompound (57 mg, 27%) was obtained as a pale-yellow powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.58-1.65 (2H, m), 1.78-1.85 (2H, m),7.03-7.09 (1H, m), 7.16 (1H, d, J=9.6 Hz), 7.47 (1H, t, J=8.1 Hz),7.52-7.61 (2H, m), 7.64-7.70 (1H, m), 7.74-7.85 (2H, m), 7.86-7.91 (1H,m), 8.06-8.18 (2H, m), 8.25 (1H, s), 8.62-8.69 (1H, m), 9.31-9.35 (1H,m), 10.45 (1H, s), 11.83 (1H, s).

Example 426 Production ofN-[6-(3-{[3-(1-cyanocyclopropyl)benzoyl]amino}phenoxy)imidazo[1,2-b]pyridazin-2-yl]pyrimidine-5-carboxamide

UsingN-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(1-cyanocyclopropyl)benzamide(140 mg, 0.313 mmol), pyrimidine-5-carboxylic acid (58 mg, 0.471 mmol),N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (90 mg,0.471 mmol), 1-hydroxybenzotriazole (63 mg, 0.471 mmol), triethylamine(60 μL, 0.471 mmol) and N,N-dimethylformamide (5 mL) as startingmaterials and in the same manner as in Example 380, the title compound(42 mg, 26%) was obtained as a pale-yellow powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 1.59-1.65 (2H, m), 1.79-1.85 (2H, m),7.03-7.08 (1H, m), 7.16 (1H, d, J=9.6 Hz), 7.47 (1H, t, J=8.2 Hz),7.54-7.60 (2H, m), 7.65-7.70 (1H, m), 7.76 (1H, t, J=2.1 Hz), 7.81-7.84(1H, m), 7.86-7.91 (1H, m), 8.15 (1H, dd, J=9.6, 0.7 Hz), 8.23 (1H, s),9.32-9.37 (3H, m), 10.46 (1H, s), 11.79 (1H, s).

Example 427 Production ofN-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}thio)phenyl]-3-(trifluoromethyl)benzamide

UsingN-{6-[(3-aminophenyl)sulfanyl]imidazo[1,2-b]pyridazin-2-yl}cyclopropanecarboxamide(140 mg, 0.430 mmol), 3-(trifluoromethyl)benzoic acid (98 mg, 0.516mmol), oxalyl chloride (75 μL, 0.860 mmol), N,N-dimethylformamide (1drop), tetrahydrofuran (3 mL) and N,N-dimethylacetamide (3 mL) asstarting materials and in the same manner as in Example 412, the titlecompound (148 mg, 75%) was obtained as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.79-0.86 (4H, m), 1.89-2.00 (1H, m), 6.96(1H, d, J=9.4 Hz), 7.34-7.39 (1H, m), 7.50 (1H, t, J=8.0 Hz), 7.79 (1H,t, J=8.0 Hz), 7.88-7.94 (2H, m), 7.98 (1H, d, J=8.0 Hz), 8.03 (1H, t,J=1.8 Hz), 8.15 (1H, s), 8.25 (1H, d, J=8.0 Hz), 8.28 (1H, s), 10.60(1H, s), 11.18 (1H, s).

Example 428 Production of3-(1-cyano-1-methylethyl)-N-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}thio)phenyl]benzamide

UsingN-{6-[(3-aminophenyl)sulfanyl]imidazo[1,2-b]pyridazin-2-yl}cyclopropanecarboxamide(140 mg, 0.430 mmol), 3-(1-cyano-1-methylethyl)benzoic acid (97 mg,0.516 mmol), oxalyl chloride (75 μL, 0.860 mmol), N,N-dimethylformamide(1 drop), tetrahydrofuran (3 mL) and N,N-dimethylacetamide (3 mL) asstarting materials and in the same manner as in Example 412, the titlecompound (108 mg, 51%) was obtained as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.78-0.87 (4H, m), 1.74 (6H, s), 1.89-1.99(1H, m), 6.95 (1H, d, J=9.4 Hz), 7.32-7.38 (1H, m), 7.49 (1H, t, J=8.0Hz), 7.60 (1H, t, J=7.8 Hz), 7.72-7.79 (1H, m), 7.86-7.96 (3H, m),8.00-8.05 (2H, m), 8.15 (1H, s), 10.45 (1H, s), 11.18 (1H, s).

Example 429 Production of3-(1-cyanocyclopropyl)-N-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}thio)phenyl]benzamide

UsingN-{6-[(3-aminophenyl)sulfanyl]imidazo[1,2-b]pyridazin-2-yl}cyclopropanecarboxamide(130 mg, 0.399 mmol), 3-(1-cyanocyclopropyl)benzoic acid (89 mg, 0.479mmol), oxalyl chloride (70 μL, 0.799 mmol), N,N-dimethylformamide (1drop), tetrahydrofuran (3 mL) and N,N-dimethylacetamide (3 mL) asstarting materials and in the same manner as in Example 412, the titlecompound (158 mg, 80%) was obtained as a pale-brown powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.78-0.88 (4H, m), 1.58-1.65 (2H, m),1.77-1.85 (2H, m), 1.89-2.00 (1H, m), 6.95 (1H, d, J=9.4 Hz), 7.32-7.38(1H, m), 7.45-7.53 (1H, m), 7.54-7.61 (2H, m), 7.82 (1H, s), 7.84-7.94(3H, m), 8.02 (1H, t, J=1.7 Hz), 8.15 (1H, s), 10.44 (1H, s), 11.18 (1H,s).

Example 430 Production ofN-{3-[(2-anilinoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide

A mixture ofN-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide(100 mg, 0.242 mmol), iodobenzene (32 μl, 0.290 mmol),tris(dibenzylideneacetone)dipalladium (0) (11 mg, 24.2 μmol),dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (23 mg, 48.4μmol), sodium tert-butoxide (34 mg, 0.362 mmol) and toluene (2 mL) wasstirred under an argon atmosphere with heating at 80° C. for 5 hr. Afterthe reaction mixture was allowed to cool to room temperature, saturatedaqueous sodium hydrogencarbonate solution was added to the mixture, andthe mixture was extracted with ethyl acetate. The extract was washedwith saturated brine, dried over anhydrous magnesium sulfate, andfiltrated. The solvent was evaporated under reduced pressure, and theresidue was purified by silica gel column chromatography (ethylacetate/hexane=0/100→50/50) to give the title compound (19 mg, 16%) as apale-green powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 6.78 (1H, t, J=7.3 Hz), 6.96-7.07 (2H, m),7.18-7.25 (2H, m), 7.36-7.50 (3H, m), 7.65-7.72 (3H, m), 7.79 (1H, t,J=7.6 Hz), 7.98 (2H, d, J=9.2 Hz), 8.18-8.32 (2H, m), 8.91 (1H, s),10.58 (1H, s).

Example 431 Production ofN-{6-[3-({[3-(trifluoromethyl)phenyl]carbamoyl}amino)phenoxy]imidazo[1,2-b]pyridazin-2-yl}cyclopropanecarboxamide

A mixture ofN-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(300 mg, 0.969 mmol), 3-(trifluoromethyl)phenyl isocyanate (667 μL, 4.84mmol), toluene (4 mL) and tetrahydrofuran (1 mL) was stirred withheating under reflux for 3 hr. After the reaction mixture was allowed tocool to room temperature, the precipitate was collected by filtrationand washed with ethyl acetate/diisopropyl ether to give the titlecompound (268 mg, 56%) as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.76-0.84 (4H, m), 1.87-1.98 (1H, m),6.83-6.89 (1H, m), 7.04 (1H, d, J=9.5 Hz), 7.23-7.40 (3H, m), 7.46-7.53(2H, m), 7.56-7.64 (1H, m), 7.95-8.00 (2H, m), 8.03 (1H, d, J=9.5 Hz),9.12-9.35 (2H, m), 11.08 (1H, s).

Example 432 Production of2-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}thio)-N-phenylbenzamide

In the same manner as in Example 278 and using2-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}thio)benzoicacid (250 mg, 0.71 mmol), aniline (184 mg, 2.0 mmol),O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (380 mg, 1.0 mmol), N,N-diisopropylethylamine (270mg, 2.0 mmol) and N,N-dimethylformamide (7 mL) as starting materials,the title compound (280 mg, 93%) was obtained as a white solid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.76-0.88 (4H, m), 1.88-1.97 (1H, m), 6.98(1H, d, J=9.5 Hz), 7.08 (1H, t, J=7.4 Hz), 7.31 (2H, t, J=8.0 Hz),7.49-7.60 (3H, m), 7.61-7.76 (3H, m), 7.88 (1H, d, J=9.1 Hz), 8.14 (1H,s), 10.51 (1H, s), 11.16 (1H, s).

Example 433 Production ofN-benzyl-2-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}thio)benzamide

In the same manner as in Example 278 and using2-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}thio)benzoicacid (250 mg, 0.71 mmol), benzylamine (212 mg, 2.0 mmol),O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (380 mg, 1.0 mmol), N,N-diisopropylethylamine (270mg, 2.0 mmol) and N,N-dimethylformamide (7 mL) as starting materials,the title compound (280 mg, 89%) was obtained as a white solid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.74-0.90 (4H, m), 1.90-2.01 (1H, m), 4.42(2H, d, J=6.1 Hz), 6.96 (1H, d, J=9.5 Hz), 7.17-7.35 (4H, m), 7.43-7.52(4H, m), 7.61 (1H, dd, J=7.0, 2.5 Hz), 7.88 (1H, d, J=9.5 Hz), 8.16 (1H,s), 9.04 (1H, t, J=5.9 Hz), 11.17 (1H, s).

Example 434 Production of2-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}thio)-N-[3-(trifluoromethyl)phenyl]benzamide

In the same manner as in Example 278 and using2-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}thio)benzoicacid (150 mg, 0.42 mmol), 3-(trifluoromethyl)aniline (191 mg, 1.2 mmol),O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (230 mg, 0.6 mmol), N,N-diisopropylethylamine (160mg, 1.3 mmol) and N,N-dimethylformamide (5 mL) as starting materials,the title compound (208 mg, 99%) was obtained as a white solid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.75-0.88 (4H, m), 1.87-1.97 (1H, m), 6.99(1H, d, J=9.4 Hz), 7.40-7.46 (1H, m), 7.49-7.63 (4H, m), 7.72-7.78 (1H,m), 7.83-7.90 (2H, m), 8.09-8.16 (2H, m), 10.85 (1H, s), 11.14 (1H, s).

Example 435 Production of2-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}thio)-N-[4-(trifluoromethyl)phenyl]benzamide

In the same manner as in Example 278 and using2-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}thio)benzoicacid (150 mg, 0.42 mmol), 4-(trifluoromethyl)aniline (191 mg, 1.2 mmol),O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (230 mg, 0.6 mmol), N,N-diisopropylethylamine (160mg, 1.3 mmol) and N,N-dimethylformamide (5 mL) as starting materials,the title compound (155 mg, 74%) was obtained as a white solid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.74-0.89 (4H, m), 1.86-1.98 (1H, m), 6.99(1H, d, J=9.3 Hz), 7.49-7.62 (3H, m), 7.67 (2H, d, J=8.7 Hz), 7.72-7.77(1H, m), 7.83-7.90 (3H, m), 8.13 (1H, s), 10.87 (1H, s), 11.14 (1H, s).

Example 436 Production of2-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}thio)-N-(1,3-dimethyl-1H-pyrazol-5-yl)benzamide

In the same manner as in Example 278 and using2-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}thio)benzoicacid (150 mg, 0.42 mmol), 1,3-dimethyl-1H-pyrazol-5-amine (130 mg, 1.2mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (230 mg, 0.6 mmol), N,N-diisopropylethylamine (160mg, 1.3 mmol) and N,N-dimethylformamide (5 mL) as starting materials,the title compound (130 mg, 70%) was obtained as a white solid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.75-0.86 (4H, m), 1.89-1.99 (1H, m), 2.08(3H, s), 3.59 (3H, s), 5.97 (1H, s), 7.00 (1H, d, J=9.8 Hz), 7.46-7.63(3H, m), 7.71-7.79 (1H, m), 7.90 (1H, d, J=9.8 Hz), 8.15 (1H, s), 10.49(1H, s), 11.17 (1H, s).

Example 437 Production ofN-[4-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}thio)phenyl]-5-methyl-1-phenyl-1H-pyrazole-3-carboxamide

Using 5-methyl-1-phenyl-1H-pyrazole-3-carboxylic acid (186 mg, 0.92mmol), tetrahydrofuran (3.0 mL), N,N-dimethylformamide (20 μL, 0.26mmol), oxalyl chloride (80 μL, 0.92 mmol),N-{6-[(4-aminophenyl)thio]imidazo[1,2-b]pyridazin-2-yl}cyclopropanecarboxamide(200 mg, 0.62 mmol) and N,N-dimethylacetamide (4.0 mL), and in the samemanner as in Example 249, the title compound (201 mg, 64%) was obtainedas a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.79-0.85 (4H, m), 1.89-1.97 (1H, m), 2.31(3H, s), 6.81 (1H, d, J=9.3 Hz), 6.89 (1H, s), 7.35-7.49 (5H, m),7.57-7.61 (2H, m), 7.76-7.86 (3H, m), 8.09 (1H, s), 10.74 (1H, s), 11.14(1H, s).

Example 438 Production ofN-{6-[4-({[(phenylacetyl)amino]thiocarbonyl}amino)phenoxy]imidazo[1,2-b]pyridazin-2-yl}cyclopropanecarboxamide

To a solution of phenylacetyl chloride (342 μL, 2.59 mmol) inacetonitrile (8.0 mL) was added potassium thiocyanate (0.31 g, 3.23mmol), and the mixture was stirred at 50° C. for 1 hr. After cooling themixture to room temperature, the solvent was evaporated under reducedpressure. Saturated brine was added to the residue, and the mixture wasextracted with ethyl acetate, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure.Toluene/ethanol (2.0 mL/2.0 mL) was added to the residue,N-[6-(4-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(200 mg, 0.65 mmol) was added to the mixture, and the mixture wasstirred at room temperature for 1 hr. Saturated brine was added to thereaction mixture, and the mixture was extracted with ethyl acetate,washed with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography (hexane/ethyl acetate=1/3)to give the title compound (164 mg, 51%) as white crystals.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.78-0.82 (4H, m), 1.87-1.95 (1H, m), 3.82(2H, s), 7.05 (1H, d, J=9.6 Hz), 7.24-7.36 (7H, m), 7.66 (2H, d, J=9.0Hz), 7.93 (1H, s), 8.02 (1H, d, J=9.6 Hz), 11.06 (1H, s), 11.71 (1H, s),12.36 (1H, s).

Example 439 Production ofN-[6-(4-{[(2E)-3-phenylprop-2-enoyl]amino}phenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide

Using (2E)-3-phenylacrylic acid (135 mg, 0.91 mmol), tetrahydrofuran(3.0 mL), N,N-dimethylformamide (20 μL, 0.26 mmol), oxalyl chloride (80μL, 0.91 mmol),N-[6-(4-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide(200 mg, 0.65 mmol) and N,N-dimethylacetamide (4.0 mL), and in the samemanner as in Example 255, the title compound (133 mg, 47%) was obtainedas a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 0.77-0.82 (4H, m), 1.86-1.96 (1H, m), 6.84(1H, d, J=15.9 Hz), 7.04 (1H, d, J=9.8 Hz), 7.25 (2H, d, J=9.0 Hz),7.38-7.50 (3H, m), 7.58-7.66 (3H, m), 7.77 (2H, d, J=9.0 Hz), 7.93 (1H,s), 8.02 (1H, d, J=9.8 Hz), 10.33 (1H, s), 11.07 (1H, s).

Example 440 Production of 2-(imidazo[1,2-b]pyridazin-6-yloxy)aniline

A mixture of 6-chloroimidazo[1,2-b]pyridazine (1536 mg, 10.0 mmol),2-aminophenol (1419 mg, 13.0 mmol), potassium carbonate (4146 mg, 30.0mmol) and N-methylpyrrolidone (10 mL) was stirred at 120° C. for 3 days.The reaction mixture was diluted with 1N aqueous sodium hydroxidesolution and extracted with ethyl acetate. The organic layer wasconcentrated under reduced pressure, and the residue was purified by NHsilica gel column chromatography (hexane/ethyl acetate=70/30→0/100). Theobjective fraction was concentrated under reduced pressure, and theresidue was purified by silica gel column chromatography (ethylacetate/methanol=100/0→75/25), and precipitated from diisopropyl etherto give the title compound (307 mg, 1.4 mmol, yield 14%) as a pale-brownsolid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 5.08 (2H, s), 6.57 (1H, td, J=7.6, 1.6 Hz),6.81 (1H, dd, J=7.9, 1.7 Hz), 6.95-7.04 (2H, m), 7.04 (1H, d, J=9.9 Hz),7.61 (1H, d, J=0.9 Hz), 8.02 (1H, s), 8.11 (1H, d, J=9.9 Hz).

Example 441 Production of methyl2-(imidazo[1,2-b]pyridazin-6-ylthio)benzoate

A mixture of 6-chloroimidazo[1,2-b]pyridazine (1536 mg, 10.0 mmol),methyl 2-mercaptobenzoate (1.788 mL, 13.0 mmol), potassium carbonate(4146 mg, 30.0 mmol) and N,N-dimethylformamide (20 mL) was stirred at70° C. for 18 hr. To the reaction mixture was added methyl2-mercaptobenzoate (0.963 mL, 7.0 mmol), and the mixture was stirred at70° C. for 6 hr. The reaction mixture was concentrated under reducedpressure, the residue was diluted with water, and extracted with ethylacetate. The organic layer was washed with water and concentrated underreduced pressure. The residue was purified by NH silica gel columnchromatography (hexane/ethyl acetate=90/10→20/80) and precipitated fromdiisopropyl ether to give the title compound (663 mg, 2.3 mmol, yield23%) as a white solid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 3.83 (3H, s), 7.14 (1H, d, J=9.5 Hz), 7.37(1H, dd, J=7.7, 1.0 Hz), 7.47 (1H, td, J=7.4, 1.4 Hz), 7.55 (1H, td,J=7.7, 1.5 Hz), 7.80 (1H, d, J=1.2 Hz), 7.95 (1H, dd, J=7.7, 1.4 Hz),8.10 (1H, dd, J=9.5, 0.6 Hz), 8.29 (1H, t, J=0.9 Hz).

Example 442 Production ofN-[2-(imidazo[1,2-b]pyridazin-6-yloxy)phenyl]-N′-phenylurea

To a solution of 2-(imidazo[1,2-b]pyridazin-6-yloxy)aniline (90 mg, 0.40mmol) and triethylamine (0.011 mL, 0.08 mmol) in tetrahydrofuran (20 mL)was added phenyl isocyanate (0.061 mL, 0.56 mmol), and the mixture wasstirred at room temperature for 18 hr. The reaction mixture wasconcentrated under reduced pressure, and the residue was recrystallizedfrom methanol to give the title compound (99 mg, 0.29 mmol, yield 72%)as a white powder.

¹H-NMR (DMSO-d₆, 300 MHz) δ 6.92-7.00 (1H, m), 7.02-7.09 (1H, m),7.17-7.30 (5H, m), 7.38-7.44 (2H, m), 7.66 (1H, d, J=6.9 Hz), 8.09 (1H,s), 8.20-8.28 (2H, m), 8.33 (1H, s), 9.04 (1H, s).

Example 443 Production of 2-(imidazo[1,2-b]pyridazin-6-ylthio)benzoicacid

To a solution of methyl 2-(imidazo[1,2-b]pyridazin-6-ylthio)benzoate(619 mg, 2.17 mmol) in methanol (20 mL) was added 8N aqueous sodiumhydroxide solution (1.00 mL), and the mixture was stirred at 70° C. for18 hr. After the reaction mixture was allowed to cool to roomtemperature, 6N hydrochloric acid (1.33 mL) was added to the reactionmixture, and the precipitated precipitate was collected by filtration,and washed with water. The precipitate was suspended in methanol (10mL), and the suspension was stirred with heating under reflux for 10min. After the suspension was allowed to cool to room temperature, theprecipitate was collected by filtration, washed with methanol, and driedunder reduced pressure to give the title compound (496 mg, 1.83 mmol,yield 84%) as a white solid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 7.15 (1H, d, J=9.5 Hz), 7.29 (1H, dd, J=7.9,1.1 Hz), 7.42 (1H, td, J=7.5, 1.2 Hz), 7.50 (1H, td, J=7.6, 1.6 Hz),7.80 (1H, d, J=1.2 Hz), 7.95 (1H, dd, J=7.5, 1.5 Hz), 8.10 (1H, d, J=9.5Hz), 8.30 (1H, t, J=0.9 Hz), 13.39 (1H, br s).

Example 444 Production of2-(imidazo[1,2-b]pyridazin-6-ylthio)-N-phenylbenzamide

To a mixture of 2-(imidazo[1,2-b]pyridazin-6-ylthio)benzoic acid (109mg, 0.40 mmol), aniline (75 mg, 0.81 mmol), 1-hydroxybenzotriazolehydrate (61 mg, 0.40 mmol) and N,N-dimethylformamide (5 mL) were added1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (153 mg,0.80 mmol) and triethylamine (0.167 mL, 1.20 mmol), and the mixture wasstirred at room temperature for 18 hr. A 1N aqueous sodium hydroxidesolution was added to the mixture and the mixture was extracted withethyl acetate. The organic layer was concentrated under reducedpressure, and the residue was purified by silica gel columnchromatography (ethyl acetate/methanol=100/0→80/20) and precipitatedfrom ethyl acetate/diisopropyl ether to give the title compound (110 mg,0.32 mmol, yield 79%) as a white solid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 6.97 (1H, d, J=9.5 Hz), 7.08 (1H, t, J=7.4Hz), 7.31 (2H, t, J=7.8 Hz), 7.51-7.76 (7H, m), 8.02 (1H, dd, J=9.5, 0.5Hz), 8.18 (1H, s), 10.51 (1H, s).

Example 445 Production ofN-[4-(imidazo[1,2-b]pyridazin-6-yloxy)phenyl]benzamide

Using 4-(imidazo[1,2-b]pyridazin-6-yloxy)aniline (113 mg, 0.50 mmol),N-methylpyrrolidone (1 mL) and benzoyl chloride (0.116 mL, 1.00 mmol),and in the same manner as in Example 145, the title compound (144 mg,0.44 mmol, yield 87%) was obtained.

¹H-NMR (DMSO-d₆, 300 MHz) δ 7.12 (1H, d, J=9.6 Hz), 7.29 (2H, d, J=8.9Hz), 7.51-7.66 (3H, m), 7.65 (1H, d, J=1.2 Hz), 7.85 (2H, d, J=8.9 Hz),7.94-8.01 (2H, m), 8.06 (1H, s), 8.17 (1H, dd, J=9.6, 0.3 Hz), 10.35(1H, s).

Example 446 Production of methyl3-(imidazo[1,2-b]pyridazin-6-yloxy)benzoate

A mixture of 6-chloroimidazo[1,2-b]pyridazine (1536 mg, 10.0 mmol),methyl 3-hydroxybenzoate (1978 mg, 13.0 mmol), potassium carbonate (4146mg, 30.0 mmol) and N-methylpyrrolidone (10 mL) was stirred at 120° C.for 18 hr. The reaction mixture was diluted with water and extractedwith ethyl acetate. The organic layer was washed with water andconcentrated under reduced pressure. The residue was purified by NHsilica gel column chromatography (hexane/ethyl acetate=90/10→20/80). Theobjective fraction was concentrated under reduced pressure, and theresidue was purified by silica gel column chromatography (hexane/ethylacetate=60/40→0/100) and precipitated from diisopropyl ether to give thetitle compound (1722 mg, 6.4 mmol, yield 64%) as a white solid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 3.87 (3H, s), 7.16 (1H, d, J=9.5 Hz),7.60-7.68 (3H, m), 7.79-7.83 (1H, m), 7.84-7.93 (1H, m), 8.05 (1H, s),8.19 (1H, d, J=9.5 Hz).

Example 447 Production of 3-(imidazo[1,2-b]pyridazin-6-yloxy)benzoicacid

To a solution of methyl 3-(imidazo[1,2-b]pyridazin-6-yloxy)benzoate(1665 mg, 6.18 mmol) in methanol (30 mL) was added 8N aqueous sodiumhydroxide solution (3.00 mL), and the mixture was stirred at roomtemperature for 18 hr and at 80° C. for 8 hr. After the reaction mixturewas allowed to cool to room temperature, 6N hydrochloric acid (4.00 mL)was added to the mixture, and the mixture was concentrated under reducedpressure. Water (30 mL) was added to the residue, and the precipitatewas collected by filtration and washed with water. The precipitate wassuspended in methanol (10 mL) and the suspension was stirred withheating under reflux for 10 min. After the suspension was allowed tocool to room temperature, the precipitate was collected by filtrationwashed with methanol and dried under reduced pressure to give the titlecompound (1045 mg, 4.09 mmol, yield 66%) as a white solid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 7.15 (1H, d, J=9.9 Hz), 7.54-7.68 (3H, m),7.74-7.80 (1H, m), 7.82-7.91 (1H, m), 8.06 (1H, s), 8.19 (1H, d, J=9.9Hz), 13.17 (1H, br s).

Example 448 Production of3-(imidazo[1,2-b]pyridazin-6-yloxy)-N-phenylbenzamide

To a mixture of 3-(imidazo[1,2-b]pyridazin-6-yloxy)benzoic acid (128 mg,0.50 mmol), aniline (56 mg, 0.60 mmol), 1-hydroxybenzotriazole hydrate(92 mg, 0.60 mmol) and N,N-dimethylformamide (5 mL) were added1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (192 mg,1.00 mmol) and triethylamine (0.209 mL, 1.50 mmol), and the mixture wasstirred at room temperature for 18 hr. 1N Aqueous sodium hydroxidesolution was added to the reaction mixture, and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (ethylacetate/methanol=100/0→75/25) and precipitated from ethyl acetate togive the title compound (122 mg, 0.37 mmol, yield 74%) as a white solid.

¹H-NMR (DMSO-d₆, 300 MHz) δ 7.11 (1H, t, J=7.4 Hz), 7.18 (1H, d, J=9.6Hz), 7.35 (2H, t, J=7.9 Hz), 7.52-7.58 (1H, m), 7.63 (1H, d, J=8.1 Hz),7.66 (1H, d, J=0.9 Hz), 7.73-7.80 (2H, m), 7.86-7.93 (2H, m), 8.07 (1H,s), 8.21 (1H, d, J=9.6 Hz), 10.28 (1H, s).

Example 449 Production of3-(imidazo[1,2-b]pyridazin-6-yloxy)-N-[3-(trifluoromethyl)phenyl]benzamide

Using 3-(imidazo[1,2-b]pyridazin-6-yloxy)benzoic acid (128 mg, 0.50mmol), 3-(trifluoromethyl)aniline (97 mg, 0.60 mmol),1-hydroxybenzotriazole hydrate (92 mg, 0.60 mmol), N,N-dimethylformamide(5 mL), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride(192 mg, 1.00 mmol) and triethylamine (0.209 mL, 1.50 mmol), and in thesame manner as in Example 448, the title compound (114 mg, 0.29 mmol,yield 57%) was obtained.

¹H-NMR (DMSO-d₆, 300 MHz) δ 7.18 (1H, d, J=9.9 Hz), 7.47 (1H, d, J=7.8Hz), 7.55-7.71 (4H, m), 7.89-7.95 (2H, m), 8.02-8.08 (2H, m), 8.19-8.25(2H, m), 10.59 (1H, s).

Formulation Example 1

A pharmaceutical agent containing the compound of the present inventionas an active ingredient can be produced, for example, according to thefollowing formulation.

1. capsule (1) compound obtained in Example 1 40 mg (2) lactose 70 mg(3) microcrystalline cellulose 9 mg (4) magnesium stearate 1 mg 1capsule 120 mg

(1), (2), (3) and 1/2 of (4) are blended, granulated and the rest of (4)is added thereto. The whole mixture is sealed in a gelatin capsule.

2. tablet (1) compound obtained in Example 1 40 mg (2) lactose 58 mg (3)cornstarch 18 mg (4) microcrystalline cellulose 3.5 mg (5) magnesiumstearate 0.5 mg 1 tablet 120 mg

(1), (2), (3), 2/3 of (4), and 1/2 of (5) are blended and granulated.The rest of (4) and (5) are added to the granules. The mixture iscompression-formed into a tablet.

Formulation Example 2

The compound (50 mg) obtained Example 1 is dissolved in JapanesePharmacopoeia distilled water for injection (50 mL), and the JapanesePharmacopoeia distilled water for injection is added to 100 mL. Thissolution is filtrated under sterile conditions. The solution (1 mL) istaken, filled in a vial for injection under sterile conditions,freeze-dried and sealed.

Experimental Example 1 Cloning of Human Vascular Endothelial GrowthFactor Receptor 2 (VEGFR2) Gene and Preparation of RecombinantBaculovirus

Human vascular endothelial growth factor receptor 2 (hereinafter to bereferred to as VEGFR2) gene was cloned by PCR using cDNA Libraries HumanPlacenta (Clontech) as a template. The primer used for PCR was preparedfrom base sequence (Genbank Accession AF035121) information of VEGFR2gene by adding a base sequence encoding flag peptide and a recognitionsequence of the restriction enzyme to a base sequence (2671-4374 ofGenbank Accession AF035121) encoding the VEGFR2 intracellular domainregion, so that the protein contains an N-terminal Flag tag. The primerbase sequence is shown below.

VEGFR2U: 5′- AATTAAGTCGACATGGACTACAAGGATGACGATGACAAGAAGCGGGCCAATGGAGGGGAACTGA (SEQ ID NO: 1) AGACA-3′ and VEGFR2-L:5′-AATTAAGCATGCTTAAACAGGAGGAGAGCTCAGTGTGGTCCC-3′ (SEQ ID NO: 2)

The base sequence of primer VEGFR2-U is shown in SEQUENCE LISTING SEQ IDNO: 1, and the base sequence of primer VEGFR2-L is shown in SEQUENCELISTING SEQ ID NO: 2.

The PCR reaction was conducted using a KOD-plus kit (TOYOBO). Theobtained PCR product was electrophoresed on agarose gel (1%), the DNAfragment amplified by PCR was recovered from the gel, and then digestedwith restriction enzymes Sal I and Sph I. The DNA treated with therestriction enzymes was electrophoresed on agarose gel (1%), and theobtained DNA fragment was recovered and ligated to plasmid pFASTBAC1(Invitrogen) digested with restriction enzymes Sal I and Sph I to giveexpression plasmid pFB-VEGFR2. The base sequence of the insert fragmentwas confirmed and found to be identical with the base sequence(2671-4374 of Genbank Accession AF035121) of VEGFR2 intracellulardomain. Furthermore, using BAC-TO-BAC Baculovirus Expression System(Invitrogen), virus stock BAC-VEGFR2 of recombinant baculovirus wasprepared.

Experimental Example 2 Preparation of Vascular Endothelial Growth FactorReceptor 2 (VEGFR2) Intracellular Domain Protein

SF-21 cells were sown at 1×10⁶ cells/mL to Sf-900II SFM medium (1 L,Invitrogen) containing 10% fetal bovine serum (trace), 50 mg/LGentamicin (Invitrogen) and 0.1% Pluronic F-68 (Invitrogen), and shakingculture was performed using a 2 L volume Erlenmeyer flask at 27° C., 100rpm. After culturing for 24 hrs, recombinant baculovirus BAC-VEGFR2(13.4 mL) was added to the mixture, and the mixture was further culturedfor 3 days. The culture medium was centrifuged at 2,000 rpm for 5 min togive virus-infected cells. The infected cells were washed with aphosphate buffered saline (Invitrogen), centrifuged under the sameconditions, and the cells were preserved at −80° C. The cryopreservedcells were thawed in ice, suspended in buffer A (50 mM Tris buffer (30mL, pH 7.4) containing 20% glycerol, 0.15 M NaCl) supplemented withComplete Protease Inhibitor (Boehringer), and ruptured 3 times with aPolytron homogenizer (Kinematica) at 20,000 rpm for 30 sec. The rupturedmedium was clarified by centrifugation at 40,000 rpm for 30 min andfiltered with a 0.45 μm filter. The filtrate was passed through a columnpacked with Anti-FLAG M2 Affinity Gel (4 mL, Sigma) at a flow rate ofabout 0.5 mL/min. The column was washed with buffer A, and eluted withbuffer A containing 100 μg/mL of FLAG peptide. The eluate wasconcentrated with Vivaspin 20 (Vivascience) having a molecular weightcut off of 30K. The buffer of this concentrate was exchanged using NAP™25 column (Amersham Bioscience) equilibrated with buffer A. Thefractions containing intracellular domain protein of VEGFR2 werecollected, glycerol was added to the final concentration of 50% andcryopreserved at −80° C.

Experimental Example 3 Cloning of Human BRAF (B-Raf) Gene andPreparation of Recombinant Baculovirus

Human BRAF gene was cloned by PCR using human Testis cDNA library(Clontech) as a template. The primer used for PCR was prepared from basesequence (Genbank Accession NM_(—)004333) information of BRAF gene byadding a base sequence encoding flag peptide and a recognition sequenceof the restriction enzyme to area encoding the BRAF kinase domainregion, so that the protein contains an N-terminal Flag. The primer basesequence is shown below.

BRAF-U: 5′- AAAGAATTCACCATGGACTACAAGGACGACGATGACAAGACCCCCCCTGCCTCATTACCTGGCT-3′ (SEQ ID NO: 3) and BRAF-L:5′- AAAAGTCGACTCAGTGGACAGGAAACGCACCATAT- 3′ (SEQ ID NO: 4)

The PCR reaction was conducted using Pyrobest (Takara Shuzo Co., Ltd).The obtained PCR product was electrophoresed on agarose gel (1%), theDNA fragment amplified by PCR was recovered from the gel, and thendigested with restriction enzymes EcoRI and SalI. The DNA treated withthe restriction enzymes was electrophoresed on agarose gel (1%), and theobtained DNA fragment was recovered and ligated to plasmid pFASTBAC1(Invitrogen) digested with restriction enzymes EcoRI and SalI to giveexpression plasmid pFB-BRAF, and the base sequence of the insertfragment was confirmed. In addition, mutation was introduced into V600Eusing a Quick change Site Directed Mutagenesis kit (Stratagene). Thenucleotide sequences of the primers used are shown in the following.

V600E-U: 5′- GGTCTAGCTACAGAGAAATCTCGATGGAG-3′ (SEQ ID NO: 5) andV600E-L: 5′- CTCCATCGAGATTTCTCTGTAGCTAGACC-3′ (SEQ ID NO: 6)The obtained plasmid was sequenced to confirm the introduction ofmutation into V600E. The plasmid was digested with restriction enzymesEcoRI and SalI, DNA was electrophoresed on agarose gel (1%), and theobtained DNA fragment was recovered and ligated to plasmid pFASTBAC1(Invitrogen) digested with restriction enzymes EcoRI and SalI to giveexpression plasmid pFB-V600E.

Using BAC-TO-BAC Baculovirus Expression System (Invitrogen), virus stockBAC-V600E of recombinant baculovirus was prepared.

Experimental Example 4 Preparation of BRAF (V600E) Protein

SF-21 cells were sown at 1×10⁶ cells/mL to Sf-900II SFM medium (1 L,Invitrogen) containing 10% fetal bovine serum (Trace), 50 mg/LGentamicin (Invitrogen) and 0.1% Pluronic F-68 (Invitrogen), and shakingculture was performed using a 2 L volume Erlenmeyer flask at 27° C., 100rpm. After culturing for 24 hrs, recombinant baculovirus BAC-V600E (13.4mL) was added to the mixture, and the mixture was further cultured for 3days. The culture medium was centrifuged at 2,000 rpm for 5 min to givevirus-infected cells. The infected cells were washed with a phosphatebuffered saline (Invitrogen), centrifuged under the same conditions, andthe cells were preserved at −80° C. The cryopreserved cells were thawedin ice, suspended in buffer A (50 mM Tris buffer (30 mL, pH 7.4)containing 20% glycerol, 0.15 M NaCl) supplemented with CompleteProtease Inhibitor (Boehringer), and ruptured 3 times with a Polytronhomogenizer (Kinematica) at 20,000 rpm for 30 sec. The ruptured mediumwas clarified by centrifugation at 40,000 rpm for 30 min and filteredwith a 0.45 μm filter. The filtrate was passed through a column packedwith Anti-FLAG M2 Affinity Gel (4 mL, Sigma) at a flow rate of about 0.5mL/min. The column was washed with buffer A, and eluted with buffer Acontaining 100 μg/mL of FLAG peptide. The buffer of this concentrate wasexchanged using NAP25 column (Amersham Bioscience) equilibrated withbuffer A and the fractions were cryopreserved at −80° C.

Test Example 1 Determination of Vascular Endothelial Growth FactorReceptor 2 (VEGFR2) Kinase Inhibitory Activity

A test compound dissolved in dimethyl sulfoxide (DMSO) was diluted witha buffer (50 mM Tris-HCl (pH 7.5), 5 mM MgCl₂, 5 mM MnCl₂, 2 mMdithiothreitol, 0.01% Tween-20). To this compound solution (5 μL) wasadded a buffer (10 μL) containing 50 ng/mL of VEGFR2 intracellulardomain protein and 250 ng/mL of biotin labeled polypeptidebiotinyl-poly-Glu:Tyr (4:1) (CIS bio International). To the obtainedmixture was added a buffer (10 μL) containing ATP (25 μM), the mixturewas allowed to react at 25° C. for 5 min and the reaction was quenchedwith 25 μL of a stop solution (100 mM EDTA disodium salt, 62.5 mM HEPESbuffer (pH 7.4), 250 mM NaCl, 0.1% bovine serum albumin, 10 μg/mLAlphaScreen assay streptavidin donor beads (Streptavidin Donor beads:PerkinElmer), 10 μg/mL AlphaScreen assay anti-phosphotyrosinerecognition antibody PY-100 binding acceptor beads (Anti-phosphotyrosine(P-Tyr-100) Acceptor beads: PerkinElmer)). The reaction solution wasallowed to stand at 25° C. for 16 hrs, and the wells were counted usinga plate reader Fusion™ (PerkinElmer). The kinase inhibitory rate (%) ofthe test compound was calculated by the following formula:Inhibitory rate(%)=(1−(count of testcompound−blank)÷(control−blank))×100

The count of the solution reacted without addition of the compound wasused as a “control”, and the count of the solution without the compoundand ATP was used as a “blank”. The inhibitory rate of the compounds ofExamples 95, 97, 103, 108, 111, 114, 117, 127, 148, 149, 150, 161, 165,173, 174, 180, 187, 208, 241, 243, 247, 254, 267, 287, 289, 298, 302,314 and 317 at 1 μM was not less than 90%.

Test Example 2 Vascular Endothelial Cell Growth Inhibitory Test

Human umbilical vein-derived vascular endothelial cells (HUVEC purchasedfrom KURABO INDUSTRIES LTD.) were cultured in an incubator at 37° C., 5%carbon dioxide in a vascular endothelial cell medium (Invitrogen)containing 5% bovine fetal serum and 2.5 ng/mL basic fibroblast growthfactor. To be specific, HUVEC was suspended in a vascular endothelialcell medium containing the aforementioned 5% bovine fetal serum andplated on a 96 well flat bottom plate by 50 μL (3000 cells) each well.After culture overnight, various concentrations of the test substanceand 120 ng/mL of vascular endothelial growth factor (VEGF) weredissolved in a vascular endothelial cell medium containing 5% bovinefetal serum and added to each well by 50 μL. After 5 days of culture, aXTT reagent (Wako Pure Chemical Industries, Ltd.) was added to each wellby 10 μL, and the mixture was reacted in an incubator at 37° C., 5%carbon dioxide for 2-3 hr. The absorbance at 450 nm was measured by amicrotiter plate reader and the cell growth inhibitory activity wasdetermined. Using the absorbance with addition of a test substance ateach concentration and based on the nonlinear least-squares analysisusing a logistic curve of SAS system NLIN procedure, the concentrationof the test substance (IC₅₀ value) necessary for showing 50% of thevalue obtained without addition of the test substance was calculated.

As a result, IC₅₀ value of the compounds of Examples 95, 97, 103, 108,111, 114, 117, 127, 148, 149, 150, 161, 165, 173, 174, 180, 187, 208,241, 243, 247, 254, 267, 287, 289, 298, 302, 314 and 317 was not morethan 500 nM.

Test Example 3 Antitumor Test

Cancer cells are cultivated in an incubator at 37° C., 5% carbon dioxidein a culture medium containing 10% bovine fetal serum. The cells areisolated by a trypsin treatment, washed with HBSS (HANK's BalancedSaline Solution) and adjusted to cell density of 5×10⁷ cells/mL withHBSS. The cell suspension (0.1 mL, 5×10⁶ cells) is transplanted bysubcutaneously injecting into the abdomen of 6-week-old female nude mice(BALB/c nu/nu, CLEA Japan, Inc.). When the tumor volume reached 100-200mm³, the mice are grouped, and orally administered with various doses oftest substance for 14 consecutive days starting from the next day. Themajor axis length and minor axis length of the tumor are measured overtime and the tumor volume is calculated from tumor volume=major axislength×minor axis length×minor axis length×0.5.

Test Example 4 Determination of Platelet-Derived Growth Factor Receptorα (PDGFRα) Kinase Inhibitory Activity

A test compound dissolved in dimethyl sulfoxide (DMSO) was diluted witha buffer (50 mM Tris-HCl (pH 7.5), 5 mM MgCl₂, 5 mM MnCl₂, 2 mMdithiothreitol, 0.01% Tween-20). To this compound solution (5 μL) wasadded a buffer (10 μL) containing 125 ng/ml of PDGFRα intracellulardomain protein (UPSTATE) and 250 ng/mL of biotin labeled polypeptidebiotinyl-poly-Glu:Tyr (4:1) (CIS bio International). At 5 min aftermixing kinase enzyme and the compound and biotin labeled polypeptide, tothe obtained mixture was added a buffer (10 μL) containing ATP (25 μM),the mixture was allowed to react at 25° C. for 30 min and the reactionwas quenched with 25 μL of a stop solution (100 mM EDTA disodium salt,62.5 mM HEPES buffer (pH 7.4), 250 mM NaCl, 0.1% bovine serum albumin,10 μg/mL AlphaScreen assay streptavidin donor beads (Streptavidin Donorbeads: PerkinElmer), 10 μg/mL AlphaScreen assay anti-phosphotyrosinerecognition antibody PT-66 binding acceptor beads (Anti-phosphotyrosine(P-Tyr-66) Acceptor beads: PerkinElmer)). The reaction solution wasallowed to stand at 25° C. for 16 hrs, and the wells were counted usinga plate reader Fusion™ (PerkinElmer). The kinase inhibitory rate (%) ofthe test compound was calculated by the following formula:Inhibitory rate(%)=(1−(count of testcompound−blank)÷(control−blank))×100

The count of the solution reacted without addition of the compound wasused as a “control”, and the count of the solution without the compoundand ATP was used as a “blank”.

The IC₅₀ value of the compounds of Examples 95, 97, 111, 148, 161, 165,173, 174, 180, 187, 208, 241, 243, 247, 267, 287, 289, 298, 302, 314 and317 was not more than 500 nM.

Test Example 5 Determination of Platelet-Derived Growth Factor Receptorβ (PDGFRβ) Kinase Inhibitory Activity

A test compound dissolved in dimethyl sulfoxide (DMSO) was diluted witha buffer (50 mM Tris-HCl (pH 7.5), 5 mM MgCl₂, 5 mM MnCl₂, 2 mMdithiothreitol, 0.01% Tween-20). To this compound solution (5 μL) wasadded a buffer (10 μL) containing 125 ng/ml of PDGFRβ intracellulardomain protein (UPSTATE) and 250 ng/mL of biotin labeled polypeptidebiotinyl-poly-Glu:Tyr (4:1) (CIS bio International). At 5 min aftermixing kinase enzyme and the compound and biotin labeled polypeptide, tothe obtained mixture was added a buffer (10 μL) containing ATP (25 μM),the mixture was allowed to react at 25° C. for 30 min and the reactionwas quenched with 25 μL of a stop solution (100 mM EDTA disodium salt,62.5 mM HEPES buffer (pH 7.4), 250 mM NaCl, 0.1% bovine serum albumin,10 μg/mL AlphaScreen assay streptavidin donor beads (Streptavidin DonorBeads: PerkinElmer), 10 μg/mL AlphaScreen assay anti-phosphotyrosinerecognition antibody PT-66 binding acceptor beads (Anti-phosphotyrosine(P-Tyr-66) Acceptor beads: PerkinElmer)). The reaction solution wasallowed to stand at 25° C. for 16 hrs, and the wells were counted usinga plate reader Fusion™ (PerkinElmer). The kinase inhibitory rate (%) ofthe test compound was calculated by the following formula:Inhibitory rate(%)=(1−(count of testcompound=blank)÷(control−blank))×100

The count of the solution reacted without addition of the compound wasused as a “control”, and the count of the solution without the compoundand ATP was used as a “blank”.

The IC₅₀ value of the compounds of Examples 97, 103, 111, 114, 117, 127,148, 149, 150, 161, 165, 173, 174, 180, 187, 208, 241, 243, 247, 254,267, 287, 289, 298, 302, 314 and 317 was not more than 500 nM.

Test Example 6 Determination of BRAF (V600E) Kinase Inhibitory Activity

A test compound (2.5 μl) dissolved in dimethyl sulfoxide (DMSO) wasadded to 37.5 μl of a reaction solution (25 mM HEPES (pH 7.5), 10 mMmagnesium acetate, 1 mM dithiothreitol) containing BRAF (V600E) enzyme(30 ng) and recombinant type protein GST-MEK1 (K96R) 250 ng, and themixture was incubated at room temperature for 10 min. ATP solution (10μl) (2.5 μM ATP, 0.1 μCi [γ-³²P]ATP) was added to the obtained mixture,and the mixture was reacted at room temperature for 20 min. The reactionwas quenched by adding 50 μL of ice-cooled 20% trichloroacetic acid(Wako Pure Chemical Industries, Ltd.). The reaction solution was allowedto stand at 4° C. for 30 min, and the acid-precipitable fraction wastransferred to GF/C filter plate (Millipore Corporation) using cellharvester (PerkinElmer). The plate was dried at 45° C. for 60 min, and40 μL of MicroScinti 0 (PerkinElmer) was added thereto. Theradioactivity was measured using TopCount (PerkinElmer). The kinaseinhibitory rate (%) of the test compound was calculated by the followingformula:Inhibitory rate(%)=(1−(count of testcompound−blank)÷(control−blank))×100

The count of the solution reacted without addition of the compound wasused as a “control”, and the count of the solution without the compoundand enzyme was used as a “blank”. The inhibitory rate of the compoundsof Examples 70, 319, 330, 398, 427 and 431 at 1 μM was not less than90%.

SEQUENCE LISTING free text

[SEQ ID NO: 1]

Designed oligonucleotide primer to amplify DNA encoding human VEGFR2

[SEQ ID NO: 2]

Designed oligonucleotide primer to amplify DNA encoding human VEGFR2

[SEQ ID NO: 3]

Designed oligonucleotide primer to amplify DNA encoding human BRAF

[SEQ ID NO: 4]

Designed oligonucleotide primer to amplify DNA encoding human BARF

[SEQ ID NO: 5]

Designed oligonucleotide primer to introduce V600E mutation

[SEQ ID NO: 6]

Designed oligonucleotide primer to introduce V600E mutation

INDUSTRIAL APPLICABILITY

The compounds (I)-(IV), a salt thereof and a prodrug thereof of thepresent invention show superior inhibitory activity on kinases such asvascular endothelial growth factor receptor and the like. Therefore, aclinically useful agent for the prophylaxis or treatment of diseasesrelated to the action of vascular endothelial growth factor in theliving body (e.g., cancer etc.) can be provided. Moreover, sincecompounds (I)-(IV), a salt thereof and a prodrug thereof of the presentinvention are also superior in efficacy expression, pharmacokinetics,solubility, interaction with other pharmaceutical products, safety andstability, they are useful as pharmaceutical agents.

This application is based on patent application Nos. 2006-213981,2006-331230 and 2007-144072 filed in Japan, the contents of which areincorporated in full herein by this reference.

1.N-[5-({2-[cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamideor a salt or a prodrug thereof.
 2. A pharmaceutical agent comprising thecompound of claim 1 or a prodrug thereof, and at least onepharmacologically acceptable carrier.